Comprehensive, up-to-date information on HIV/AIDS treatment, prevention, and policy from the University of California San Francisco

HIV-1 and the less common HIV-2 belong to the family of retroviruses. HIV-1 contains a single-stranded RNA genome that is 9 kilobases in length and contains 9 genes that encode 15 different proteins.(36,37) The major viral proteins (some of which contain >1 protein subunit) are classified as structural proteins (Gag, Pol, and Env), regulatory proteins (Tat and Rev), and accessory proteins (Vpu, Vpr, Vif, and Nef).

Three major classes of HIV-1 have emerged: M (main), N (new), and O (outlier). Among M group viruses, which account for >90% of HIV infections worldwide, there are 9 subtypes, called clades, designated by the letters A-D, F-H, J, and K, as well as many recombinant forms.(38,39) Variation between one clade and another in the amino acid sequences of the envelope protein may exceed 30%. Clade B, the most common subtype in the Americas and Western Europe, differs considerably from those clades found in Asia and Africa, where the majority of HIV-infected individuals reside (see Figure 1). Viral diversity is greatest in sub-Saharan Africa. To date, most HIV drug development has targeted clade B. As HIV treatment is extended into regions where non-B clades predominate, issues of differential drug response, drug mutation patterns, and reliability of viral testing (ie, viral loads and resistance testing) may emerge.(40,41) Sequence diversity among various clades also needs to be considered in vaccine development, as most HIV-specific neutralizing antibodies (42) and some cytotoxic T-lymphocyte (CTL) responses (43) are type specific.

HIV infection of a host cell begins with the binding of the virus particle (virion) to the host cell. This process is initiated when the surface envelope protein (Env, which consists of 3 copies each of the 2 subunit proteins gp120 and gp41) engages its primary receptor, the CD4 molecule on the surface of the target cell.(44) Initial binding to CD4 exposes another portion of the Env trimer, which then binds to a coreceptor, usually the chemokine receptor CXCR4 (in the case of T-cell-tropic, or syncytium-inducing strains of HIV) or the chemokine receptor CCR5 (in the case of macrophage-tropic, or nonsyncytium-inducing strains).(45) This coreceptor binding causes the gp41 trimer portion of the envelope molecule to spring open and "harpoon" the lipid bilayer of the target cell membrane. The "hairpin" domains of gp41 then fold together to pull the virus and host cell membranes together, allowing fusion to occur.(46) The viral contents, including copies of the viral genetic material and the Pol protein (reverse transcriptase, or RT) thus enter the cytoplasm of the host cell. Reverse transcription, that is, the copying of the viral genetic material from RNA into DNA can then occur.

The preintegration complex (PIC), composed of the copied DNA (cDNA) and a number of viral and host proteins, then enters the cell nucleus, where the viral enzyme integrase mediates the insertion of the viral cDNA into the host chromosomal DNA.(47) The resulting integrated DNA virus (also called a provirus, to distinguish it from the virion form) may remain latent for hours to years before becoming active through transcription (copying of DNA into RNA).(48) Transcription of the viral genome is under complex control of a number of proteins, including Tat and cellular DNA transcription factors.(49) Transport of the transcribed viral RNA out of the nucleus also depends on a number of host and viral factors, including Rev.(50) The transcribed viral RNA may be transported out of the nucleus in its full-length form to serve as genetic material for new virions, or it may be partially or fully spliced. The unspliced, partially spliced, and fully spliced versions of viral RNA direct the synthesis of different viral proteins by the cell ribosomes. New viral particles are assembled at the plasma membrane and incorporate Gag subunits, Pol, Nef, Env, Vpr, and viral genomic RNA.(51) The HIV viral protease enzyme acts following virion assembly to cleave viral proteins into functional structural and enzymatic components. Gag then functions in the budding of mature virions from the plasma membrane.(52) The Nef protein acts on the cellular environment to promote replication by inhibiting the host immunologic response to HIV (53-55) and inhibiting death of infected cells by apoptosis.(56)

Current HIV therapies inhibit the viral replication process at the binding and entry stage (fusion inhibitors), the reverse transcription stage (nucleoside and nonnucleoside reverse transcriptase inhibitors [NRTIs and NNRTIs, respectively]), or the protein cleavage stage (PIs). Inhibitors of coreceptor binding, integration, and maturation are in clinical trials.

Individuals infected with HIV show both cellular and humoral (antibody) immune responses to the virus, but these responses are unable to prevent the ultimate progression of disease in the great majority of infected individuals. Cellular responses are mediated by CTLs (CD8 cells) and helper T lymphocytes (CD4 cells). CTLs inhibit HIV replication both directly, by recognizing and killing infected cells, and indirectly, by producing soluble chemokine antiviral factors.(57,58)

CTL-mediated killing of virally infected host cells occurs through direct contact, whereby the T-cell receptor on the surface of the CTL recognizes a fragment (epitope) of an HIV protein bound to a major histocompatibility complex (MHC) class I molecule on the surface of the infected host cell. After this interaction, the CTL releases enzymes that kill the infected cell. CTL responses directed against certain epitopes of the Gag protein have been associated with slower HIV disease progression than CTL responses against other epitopes.(59) CTLs also exert effects through soluble factors such as RANTES, macrophage inflammatory protein (MIP)-1-alpha, and MIP-1-beta, which inhibit HIV from infecting new cells by blocking HIV coreceptors.(60)

CD4 responses to HIV are important in viral control, and strong HIV-specific CD4 responses are associated with lower HIV viral loads.(61) CD4 cells respond to HIV antigens presented in conjunction with MHC class II molecules on the surface of infected cells. The fact that HIV infects CD4 cells themselves is an evolutionary strategy with a number of consequences. Because productive HIV infection occurs in activated CD4 cells, infection and killing of CD4 cells that are responding to HIV infection itself may cause a selective decrease in the number of HIV-specific CD4 cells. (HIV can also exist in nonactivated CD4 cells in a preintegrated form, which can become integrated if activation occurs within a few days.[62]) Additionally, as some of the activated, infected CD4 cells differentiate into resting memory CD4 cells, they may carry copies of the HIV genome in a postintegrated form that can persist for decades.(63) Current antiretroviral medications cannot efficiently eliminate the virus from cells in the resting state, leading to persistence of infection even in the presence of suppressive therapy.(63) Moreover, HIV continues to evolve under the selection pressure of the immune response that occurs in each infected individual, and mutations in the viral epitopes recognized by the immune system may enable the virus to escape the control of even broad and robust CD4 and CD8 HIV-specific responses.(64)

Depletion of CD4 lymphocytes is the hallmark of HIV infection, and predicts an individual's risk for infection with opportunistic pathogens as well as other complications of HIV disease. Evidence has shown that both increased peripheral destruction and decreased production of CD4 cells likely play a role in this decline.(65-69)

Humoral immunity appears to be less effective in controlling viremia than cellular responses, as HIV is remarkably effective at evading host antibody responses, and broadly neutralizing antibodies are rare.(70,71) The difficulty in eliciting broadly neutralizing antibody responses against HIV has posed a particularly difficult challenge to the development of a protective HIV vaccine.

Primary HIV infection is defined as the time period from initial infection with HIV to the development of an antibody response detectable by standard tests. Data from careful prospective evaluations of populations at risk for HIV infection demonstrate that up to 87% of individuals who acquire HIV may experience some symptoms of primary HIV infection.(107) The acute viral syndrome of primary HIV infection (sometimes referred to as "seroconversion illness") was first defined in 1985, with symptoms resembling those of mononucleosis appearing within days to weeks following exposure to HIV.(108,109). Symptoms may be mild or severe and may last from a few days to several weeks, with the average duration being 14 days. The most common presenting symptom is fever, seen in over 75% of patients.(110) Other commonly reported symptoms include fatigue, lymphadenopathy, headache, and rash. The rash, which is present in 40-80% of cases, may be evanescent, is typically maculopapular in character, and typically involves the trunk.(110) Evaluation of cohorts from Kenya (111) and India (112) found more frequent reports of joint pains, night sweats, and mucosal candidiasis and less frequent rash and pharyngitis in these study populations. A more severe clinical syndrome in primary HIV infection has been associated with a more rapid subsequent clinical course of HIV disease.(113)

The nonspecific symptoms of primary HIV infection may make diagnosis a challenge. In a study of high-risk individuals presenting with symptoms consistent with primary HIV infection, only 25% were diagnosed during their initial presentation.(107)

Diagnosis of HIV during the acute seroconversion phase requires not only high clinical suspicion but also an understanding of appropriate testing strategies. Routine HIV antibody testing may be negative for several weeks or even months after exposure in the so-called "window period."(114) During primary infection with HIV, plasma viral load often reaches very high levels in the range of millions of RNA copies/mL.(115,116) Thus, for individuals in whom primary HIV infection is clinically suspected, HIV RNA assays, which have a sensitivity approaching 100% and specificity of 97.4% in this setting,(117) should be included in the diagnostic evaluation. HIV RNA tests are not licensed for the diagnosis of HIV infection, and positive RNA tests during acute infection should be confirmed by documentation of subsequent HIV antibody conversion. The high levels of viremia seen in primary infection do not persist, however,(116) providing evidence of a host immune response capable of bringing the infection under some degree of control, at least in the short term.

During primary HIV infection, HIV-specific CD8 cells undergo a marked clonal expansion and express high levels of activation markers such as CD38 and human leukocyte antigen (HLA)-DR.(118) The breadth and strength of this CTL response correlate positively with the degree of viral control and inversely with the rapidity of clinical progression.(119-122)

CD4 counts and CD4 function may decline during primary HIV infection, occasionally to levels that allow OIs to develop.(123-125) Absolute CD4 count often rebounds after the primary infection, but may not return to a normal baseline. In patients with clinical progression of HIV disease, CD4 responses against HIV itself appear to remain particularly impaired following primary infection.(126)

After the initial reduction of viremia, a viral "set-point" is established in each infected individual. The magnitude of this set-point correlates with the rate of progression of HIV disease (see Table 5).(31,127,128) Studies of individuals during primary HIV infection have raised the question of whether the set-point might be reduced by early treatment.(129) Although early antiretroviral therapy may preserve immune function,(130) rapid control of viremia may also inhibit the full development of a mature immunologic response.(131) Carefully supervised interruptions of antiretroviral treatment after initial control during acute infection may permit the development of an effective immune response in the short term,(129) but long-term follow-up suggests that increases in viral load and emergence of drug resistance may occur in such patients.(132) The best strategy for treatment of acute HIV infection remains a matter of investigation.

After the period of acute HIV infection--during which CD4 counts and viral load change dramatically--a relative equilibrium between viral replication and the host immune response is reached, and individuals may have little or no clinical manifestations of HIV infection. This time between initial infection and the development of AIDS may be long, averaging 10 years, even in the absence of treatment.(133)

Despite the relative clinical latency of this stage of HIV infection, viral replication and CD4 cell turnover remain active, with millions of CD4 cells and billions of virions produced and destroyed each day.(28) During this period, most infected individuals will have progressive loss of CD4 lymphocytes and perturbation of immune function.(134-137) On average, CD4 counts will drop by 50-90 cells/µL per year in asymptomatic individuals, usually with an acceleration of this rate over time.(138)

The rate of progression of infection may vary considerably. In adults, progression from infection to clinical AIDS is rare in the first 2 years of infection; however, reports describe rapid disease progression in infants infected by blood transfusion.(139) In a well-characterized cohort of HIV seroconverters who were identified in a retrospective analysis of stored serum samples from hepatitis B vaccine trials in the 1970s, 87% of infected individuals had developed AIDS by 17 years postseroconversion. Twelve percent maintained a CD4 count >500 cells/µL at 10 years, but only 3% maintained a CD4 count >500 cells/µL at 16 years after seroconversion.(140)

During chronic HIV infection, HIV RNA levels in plasma correlate with the rate of CD4 decline, with higher plasma viral loads predicting more rapid progression to AIDS and death.(141,142) An undetectable HIV RNA level in peripheral blood is associated with stable CD4 lymphocyte counts, and increases in HIV RNA correlate with more rapid rates of CD4 cell decline.(143,144)

The analogy of a train on a track (attributed to John Coffin of Tufts University, circa 1996) has been helpful in illustrating the independent contributions of CD4 count and HIV viral load in an individual person. If the infected individual is imagined as being on that train traveling toward a clinical event--such as acquiring an OI or dying from AIDS--the CD4 count provides information on the distance of the train from that destination, whereas the viral load provides information on the speed of the train in reaching the destination (see Figure 2).

According to CDC criteria (see Table 1 and Table 2), AIDS is defined by either diagnosis of one of the AIDS-defining conditions, or by measurement of CD4 levels <200 cells/µL. Progression to AIDS from time of infection occurs, on average, 2 years earlier when defined by laboratory criteria (CD4 levels <200 cells/µL) compared to clinical criteria (development of an opportunistic illness).(145,146) Survival time from the development of AIDS varies according to the AIDS-defining event. In the Multicenter Hemophilia Cohort Study, median survival after a single AIDS-defining condition ranged from 3 to 51 months for the 10 most common conditions.(147) The mean survival time after diagnosis of AIDS in the United States prior to the availability of antiretroviral treatment was 10-12 months.(147)

(See chapter "HIV Antibody Assays")

HIV infection is usually diagnosed by testing serum for antibodies to HIV using a commercially available enzyme-linked immunosorbent assay (ELISA or EIA). Because the ELISA test is not entirely specific, positive results are confirmed with a Western blot assay, which identifies antibodies to specific components of HIV.(192,193). The 2-step process may mean that a patient must wait for a week or more to receive test results.

ELISA is quite sensitive in chronic HIV infection (although decline in antibody responses have been reported in advanced AIDS), but because antibody production does not occur immediately upon infection, an infected individual may test ELISA negative during a "window period" that varies in length from a few weeks to a few months after infection, depending on the individual case and assay used. Despite negative antibody testing during this window period, an individual may have high viral load and be at high risk of transmitting infection.

Newer methodologies allow antibody testing on saliva (194,195) and urine (195,196) specimens, although positive results should be confirmed with serologic testing. Home testing methods are also available.(197) Rapid HIV serum testing, with results available in 3-30 minutes, has shown 99-100% sensitivity and specificity compared to ELISA when tested in clinical settings,(198) including in resource-poor settings (199-201) and in pooled specimens.(202) In recent years, with the availability of rapid tests such as OraQuick (Abbott Laboratories, Abbott Park, IL) and Reveal (MedMira, Halifax, Nova Scotia, Canada), rapid testing protocols are being implemented in many countries, and will likely become commonplace.

"Detuned" Antibody Testing

By decreasing the sensitivity of ELISA assays, relatively recent infection (in which antibodies are present in lower concentrations and bind to HIV less effectively) can be distinguished from established infection (in which antibodies reach stable levels and have been selected for more avid binding to HIV). Soon after infection (but after the window period) an individual will test positive on the standard ELISA, but negative on the less-sensitive ("detuned") test. After maturation of the antibody response, both tests will give a positive result. Such "sensitive/less sensitive" or detuned ELISA testing strategies can be used to identify individuals who are in the early months of HIV infection and can help to identify incident infections in epidemiologic studies.(203,204)

The CD4 cell count in blood correlates with the risk of OIs in HIV disease,(205,206) and is therefore a useful marker for HIV disease staging. CD4 count is the main criterion for clinical decision making in guidelines developed in the United States for the prophylaxis of OIs (24,207) and for HIV treatment.(208)

The CDC recommends CD4 testing every 3-6 months in all HIV-infected persons,(209) but different intervals may be appropriate to the individual case. More than 1.6 million CD4 cell measurements are performed annually by approximately 600 testing laboratories in the United States.(210)

Because CD4 cells are a subset of all T lymphocytes, which are in turn a subset of all white blood cells, variations in CD4 count can occur in response to a variety of variables including concurrent infection, medications, stress, malnutrition, vitamin deficiencies, and normal diurnal variation. Often, these variables affect many subsets of lymphocytes and not exclusively CD4 cells; thus, the percentage of T lymphocytes that are CD4 positive will remain relatively stable. On the contrary, the depletion of T lymphocytes in HIV disease primarily affects CD4 cells, causing a relative CD4 cytopenia and a drop in the CD4 cell percentage. Additionally, an inversion of the normal CD4/CD8 cell ratio, which is usually >1 in non-HIV-infected individuals, may be seen with progressive CD4 cell depletion due to HIV. Thus, the CD4 percent and the CD4/CD8 ratio may help the clinician determine if a change in absolute CD4 count is due to the effects of HIV disease or to some other factor.

Until recently, most absolute CD4 cell counts were determined using 2 instruments, a hematology analyzer and a flow cytometer (dual-platform technology [DPT]). The CD4 count produced from DPT is the product of 3 laboratory measurements: the white blood cell count, the percentage of white blood cells that are lymphocytes (differential), and the percentage of lymphocytes that are CD positive (determined by flow cytometry). Single-platform technology (SPT) is designed to enable determinations of both absolute and percentage lymphocyte subset values using a single tube.(211) SPT, introduced for clinical application in 1996 is becoming the preferred method of CD4 count determination in a number of laboratories.(212)

Both SPT and DPT flow cytometry technology for CD4 count determination require specialized equipment and technician training. In resource-limited settings where CD4 count may be unavailable, the total lymphocyte count (TLC), which can be determined simply and cheaply, may be used as a surrogate for CD4 in determining stage of HIV infection.(213-215) For example, in a cohort of HIV-positive people in south India, a TLC of <1,400 cells/µL has been shown to be a good predictor of a CD4 count <200 cells/µL and thus an appropriate surrogate marker for initiating cotrimoxazole prophylaxis.(215) TLC may also have applications in monitoring response to antiretroviral therapy in place of or in conjunction with CD4 count. In an analysis of patients initiating a triple antiretroviral drug regimen, an increase in TLC was associated with an increase in CD4 count and a decrease in plasma viral load.(216)

(See chapter "HIV Viral Load Assays")

Three technologies exist to measure HIV viral load in serum: reverse transcription polymerase chain reaction (RT-PCR), branched DNA (bDNA), and nucleic acid sequence-based amplification assay (NASBA). The basic principles underlying these assays are similar--HIV is detected using DNA sequences that bind specifically to those in the virus--but results may vary between tests. Whereas early versions of the bDNA and RT-PCR techniques showed 2- to 2.5-fold differences in results, the version 3.0 bDNA assay and version 1.5 RT-PCR test yield values that are highly correlated (r = 0.96) and in good agreement (92.7%).(217,218) Testing of non-clade B HIV-1 viruses using these methods may not yield such highly correlated results.(219) Thus, it is advised that clinicians consistently use the same test when possible to compare results over time.

Because viral load may vary by orders of magnitude, results of viral load testing are often expressed in log units, where each increase of 1 log corresponds to a factor of 10. Thus, a viral load of 1,000 would be 3 log units, and the difference between a viral load of 1,000 and 10,000 would be 1 log unit. A change in viral load of >0.5 log copies/mL (approximately 3-fold) exceeds assay and diurnal variations, and may be considered to represent a true biological event, whereas a change of <0.5 log copies/mL cannot be distinguished from random variability. Diurnal variation in stable HIV viral loads is approximately 0.4 log copies/mL.(220) Acute intercurrent infection (221) or immunization (222,223) may also transiently increase viral load.

Assays for HIV antigens, notably the p24 antigen encoded by the gag gene, can be used to screen donated blood products.(224) Measurement of p24 antigen may also be a less expensive yet effective alternative to HIV RNA testing in monitoring response to treatment.(225) Testing for p24 may also be used to diagnose early HIV infection, because this viral antigen can be detected in the blood of infected individuals prior to the development of antibodies (seroconversion) detectable by ELISA or Western blot tests. In identifying primary HIV infection, p24 is more specific (99% vs. 95-97%) but less sensitive (79% vs. 100%) than HIV RNA determinations (either PCR or bDNA).(117)

(See chapters "Assays for Antiretroviral Resistance" and "Genotypic Testing for HIV")

Resistance to antiretroviral drugs is unfortunately common in treated populations. Resistance testing can be useful in determining which drugs not to use in a treatment-experienced patient whose viral load is increasing despite therapy, or in a previously untreated individual who may have been infected with HIV resistant to one or more drugs.

Two types of HIV resistance testing are available. Genotypic assays detect genetic mutations in the coding regions of the protease and reverse transcriptase enzymes in HIV isolated from the patient. Using the results, standardized algorithms are applied to predict resistance to various antiretrovirals. Phenotypic assays are more similar to standard bacteriologic sensitivity assays in that they are performed by culturing a fixed inoculum of HIV genetic material isolated from the patient with serial dilutions of individual antiretroviral drugs.

Prospective trials of genotypic (226-228) and phenotypic (229) assays have shown benefit with each of these assays in achieving virologic control in patients failing antiretroviral regimens. Additionally, with increasing incidence of drug resistance in individuals recently infected with HIV,(230) resistance testing during acute or early HIV infection may have important long-term clinical relevance. Resistance testing in chronically HIV-infected individuals provides information only on resistance to the medications being taken at the time of the test. In individuals who have changed or interrupted antiretroviral treatment, HIV harboring resistance mutations selected by prior treatment may be "archived" as proviral DNA in long-lived resting lymphocytes or macrophages, and may not be detected by resistance tests. Archived strains, however, can be expected to return to dominance if selected by the drugs to which they possess resistance. Results of resistance testing are therefore not a substitute for the patient's clinical antiretroviral history, which must also be taken into account. Further, because many resistance mutations tend to become outgrown by wild-type virus when the drug in question is no longer present to select for the resistance mutation, resistance testing in chronically infected individuals who are not on ART at the time of testing is unlikely to be of use and may provide misleading information.

In general, genotypic assays are more easily available, cheaper, and more rapidly performed than phenotypic assays. A genotype result is more likely than a phenotype to detect resistance from a minor variant or population mixture. Genotype testing identifies only the dominant strains representing >10-20% of virus circulating in blood at the time of testing.(231,232). Genotypic assays require an HIV viral load of >1,000 copies/mL to be reliable. Different laboratories use different algorithms for determining drug resistance from a given genotype result, and those different algorithms often produce discordant results, particularly for NRTIs.(233)

A phenotypic resistance test has the advantage that results are generated in a minimal inhibitory concentration (MIC) format that is more familiar to many clinicians and also emphasizes the gradation of resistance that often exists; however, the phenotypic threshold value that correlates with clinical resistance is still debated for certain antiretrovirals. A phenotype gives results for one drug at a time and is unable to predict the effects of combinations of drugs. Phenotypic resistance assays may be particularly useful when combined with monitoring of drug levels in treating individuals with highly resistant virus.

The "virtual phenotype" approach combines databases of matched genotypes and phenotypes from the same viral isolates to predict the phenotypic susceptibility of viruses with known genotypic sequences.

Current guidelines in the United States recommend resistance testing in cases of acute or recent HIV infection, for certain patients who have been infected as long as 2 years or more prior to initiating therapy, in cases of antiretroviral failure, and during pregnancy.(234)

It is worth reemphasizing that, given the limitations of all currently available resistance assays to detect archived mutations and minor variants, results of resistance testing must always be interpreted in the context of prior antiretroviral history and previous resistance testing.

The measurement of antiretroviral drug concentrations in patient serum may be used to predict toxicity,(235) maximize efficacy,(236) assess effects of drug-drug interactions,(237,238) and provide evidence regarding medication adherence.(239)

Therapeutic drug monitoring (TDM) requires proper timing of sampling relative to dosing and meals, and sampling the appropriate body compartment. For PIs and NNRTIs, drug concentrations are measured in the plasma compartment, whereas for nucleoside and nucleotide reverse transcriptase inhibitors, measurement of intracellular metabolites is necessary.

In general, data on the efficacy of TDM in clinical practice are mixed. In certain circumstances, such as in pregnant or pediatric patients, TDM may provide data on drug concentrations that have not otherwise been well characterized, but data from large studies are lacking to support its routine use in clinical care.(240)

ELISA or HIV viral load testing of fluids other than blood (seminal and vaginal fluid, cerebrospinal fluid, urine, and saliva) are currently available or under investigation. The clinical applications of some of these methods are well proven (ie, diagnosis of HIV infection with saliva or urine ELISA testing [241]), whereas for others it is less so (ie, serum viral load as a predictor of infectivity [242] or testing of semen for use in in vitro fertilization [243]).

Various culture techniques are available to isolate HIV from patient specimens.(244) HIV can be quantitated by determination of proviral DNA in peripheral blood mononuclear cells.(245) Proviral DNA has been used to test babies for HIV infection who were born to HIV-positive mothers.(246)

Assays of HIV antigens, notably p24 antigen, can be used to screen donated blood products.(224) It may also be an effective, inexpensive alternative to HIV RNA testing in monitoring response to treatment.(225) Additionally, because it is a direct viral antigen, p24 can be detected in the blood of infected individuals prior to the seroconversion detected by ELISA or Western blot tests. When comparing p24 antigenemia to HIV RNA determinations (either PCR or bDNA) in identifying primary HIV infection, p24 is equally specific (99% vs. 95-97%) but less sensitive (79% vs. 100%).(117)

(See "Overview of Antiretroviral Drugs" )

Currently, all FDA-approved antiretroviral medications work by inhibiting 1 of 3 steps in the life cycle of HIV:

1. Blocking the reverse transcriptase (RT) enzyme. The RT enzyme is used by the virus to convert its RNA into DNA after the virus enters the cell but before it enters the nucleus. All nucleoside and nucleotide analogues as well as NNRTIs function by interfering with the activity of this enzyme.

2. Blocking the protease enzyme. Protease inhibitors, as their name indicates, inhibit the action of the HIV protease, namely, cleaving protein products of the viral structural genes into the functional subunits needed to create new infectious virions.

3. Inhibiting fusion of the viral and host membranes. By attaching itself to the HIV envelope glycoprotein gp41, fusion inhibitors prevent formation of the "hairpin" structure (see "Virology", above) required for fusion of the HIV and host cell membranes, and thus prevent viral entry into the host cell.

New antiretroviral medications that are in development include improved formulations of currently approved drugs (to enhance bioavailability, increase half-life, or reduce adverse effects); new drugs in the same classes as currently approved drugs (such as PIs or NNRTIs with fewer adverse effects or unique resistance patterns); and drugs with novel mechanisms of action (eg, integrase inhibitors, entry inhibitors, and HIV coreceptor blockers).

Not all HIV-infected individuals require ART at a given point in time. For those whose CD4 count and clinical assessment indicate a low risk of imminent disease progression, the potential adverse effects of immediate treatment would be expected to outweigh any benefit. Others may have psychosocial barriers to adherence that preclude effective ART, at least in the short term, until conditions related to these issues can be improved (eg, through stable housing, substance abuse counseling, or treatment of medical or psychiatric conditions). Because incomplete adherence can rapidly lead to lasting resistance against available antiretrovirals, it is usually worthwhile to address issues that are likely to impair adherence before starting ART. Still other individuals may opt for complimentary/alternative medicine (CAM) for management of their disease. In one large population-based study, 3% of individuals with HIV chose to use CAM as a substitute for standard therapy.(247) Unfortunately, there is no convincing evidence that CAM is effective in improving clinical status or survival in HIV infection.

Individuals for whom initiation of ART is not indicated must be monitored closely for changes in immune status (eg, CD4 counts) that might signal increased risk of OIs and thus trigger initiation of ART, OI prophylaxis, or other intervention.(24,207) In general, determination of CD4 counts and viral loads should be made every 3-6 months in individuals with stable infection. Measurements of CD4 count may be transiently decreased and measurements of HIV viral load transiently increased during acute infection with another pathogen (248-251) or immediately after vaccination,(252-255) and providers should avoid measurement of these parameters in such situations.

The decision to initiate (or reinitiate) ART should be made with clear goals that address the concerns of the patient as well as the provider. Active viral replication in the presence of antiretroviral drugs can be expected to result in selection of drug-resistant virus leading ultimately to treatment failure. Therefore, any antiretroviral regimen should ideally be prescribed with the intention of complete viral suppression. When complete suppression is not possible, secondary goals of treatment may include partial virologic suppression (which might be the best attainable goal if the virus is highly resistant to antiretrovirals), immunologic reconstitution, or alleviation of symptoms (such as fever, night sweats, or weight loss). Sufficient patient education on the antiretroviral regimen chosen--dosing schedule, meal restrictions, anticipated adverse effects and adverse effect management--is also crucial to the success of any treatment regimen. Individual adherence is one of the most challenging and most important aspects of treatment success.(256,257)

In initiating or changing an antiretroviral regimen, patients and clinicians must be aware of the development of potential drug adverse effects or toxicities--in both the short and long term (see Table 4).

The efficacy of an antiretroviral regimen should be monitored by regular determinations of HIV viral load and CD4 count. The first indication of successful treatment is a decline in viral load. The decline in viral load is biphasic.(258) The first (fast) decay phase occurs during the first 2 weeks of treatment for most patients; a second (slow) phase of decay is evident thereafter. The first phase may result primarily from antiviral effects of medications, whereas immune factors such as CTL antiviral activity may contribute to the elimination of virally infected cells in the second phase.(259) The kinetics of response are variable among individuals, and do not appear to be entirely determined by adherence or drug levels. Moreover, although viral decay rates are not entirely predictive of subsequent virologic failure,(259) virologic response at 4 weeks of treatment has been shown to correlate with response at 48 weeks.(260) As a rule of thumb, in a successful regimen the viral load should decline by at least 1 log by 4 weeks after treatment initiation; slower rates should prompt closer assessment of patient adherence, viral resistance, and possible drug-drug interactions. Even a successful regimen, however, may take 4-6 months or even longer to attain undetectable viral loads.

As viral load declines, the number of circulating CD4 cells begins to increase. Initial increases in CD4 count during the first 1-3 months of therapy are believed to be caused primarily by a redistribution of cells trapped from lymphoid tissue.(261) The subsequent rate of improvement in CD4 levels is variable among individuals, and gradual CD4 count increases may continue for many years with therapy that effectively suppresses HIV replication.(262-264) Individuals with lower nadir CD4 counts may have a slower and less complete CD4 recovery, whereas those who start therapy with higher CD4 counts and maintain continued viral suppression with antiretroviral medications may reach CD4 counts similar to those of HIV-uninfected individuals.(264)

As the immune system begins to reconstitute itself in the early phases of ART, it may mount vigorous inflammatory responses against certain pathogens. The restoration of immune function may therefore cause paradoxical worsening of certain coexisting OIs, a phenomenon known as "immune reconstitution syndrome." Infections for which immune reconstitution syndrome has been reported include pneumocystosis,(265) cryptococcosis,(266) cytomegalovirus (CMV) retinitis,(267) Mycobacterium avium complex infection,(268) and tuberculosis.(269) Immune reconstitution syndrome generally presents as inflammation of tissues involved in the infection (eg, marked lymphadenopathy in tuberculosis, potentially sight-threatening inflammation of the vitreous in CMV retinitis), presumably reflecting localized antigen load. The syndrome appears to occur most frequently in individuals with low CD4 counts and develops in the initial weeks of ART. It may present a diagnostic challenge to the clinician, and should be evaluated thoroughly to exclude other etiologies such as failure of therapy or other infections. Exact diagnostic criteria and guidelines for management of immune reconstitution syndrome are being developed. No clear guidelines for the management of immune reconstitution syndrome exist; however some approaches include using systemic corticosteroid treatment, or stopping antiretrovirals in the most severe cases. For more information on immune reconstitution inflammatory syndromes, see "Clinical Implications of Immune Reconstitution in AIDS".

Antiretroviral regimens may fail to suppress viral replication for a number of reasons, including incomplete adherence, poor absorption, toxicity leading to missed or lowered doses, pharmacokinetic interaction, suboptimal antiviral potency, and preexisting drug resistance. Virologic failure has been reported in as many as 63% of patients in population-based studies.(270,271) However, virologic outcomes may be improving over time; in a recent large cohort study, 72% of subjects on therapy attained HIV RNA <500 copies/mL at 6 months.(272)

At the time of changing antiretroviral regimens, careful assessment of the reasons for changing should be undertaken. Understanding the factors of adherence, toxicity, and resistance that prompted the switch will aid in designing subsequent regimens and optimizing patient outcomes. Changes to regimens for reasons of toxicity may be as simple as exchanging a new drug for the one that was causing the toxicity, provided that virus resistant to the other drugs in the regimen has not emerged. Patients who have failed multiple regimens or who have highly drug-resistant virus may require a more complicated "salvage" regimen. Such regimens may contain more drugs, may involve more complicated dosing schedules and may include experimental agents. Complete viral suppression may not be an achievable goal in some patients, decisions to change or continue treatment should take into account immunologic and clinical stability,(217) as well as the observation that selective pressure by antiretrovirals can maintain drug-resistant mutations that impair viral RC.(273,274)

Situations arise when interruption of therapy is necessary in a given patient--toxicity, severe illness, and other circumstances making adherence impossible. In these situations, clinicians and patients should be aware of the recommendations to stop all antiretrovirals at once (or possibly stagger according to each drug's half-life) to minimize the possible emergence of resistance.(35)

Intentional supervised (or structured) treatment interruption (STI) presents several theoretical benefits: minimizing drug exposure, possibly decreasing short- and long-term adverse effects; "autovaccinating" individuals with their own virus in hopes of boosting the host immune control of HIV; allowing reversion of resistant virus to wild type, potentially creating a more drug-sensitive target for salvage therapy; and reducing the cost of therapy.

Studies conducted thus far demonstrate that STI does not increase HIV-specific immune response by acting as "autoimmunizations," and does not lead to persistent control of viremia.(275-281) A possible exception is in the unique situation of treatment during acute infection.(129,282) Studies of STI in conjunction with immune modulators such as interleukin (IL)-2 or therapeutic vaccination are underway.

A trial of intermittent therapy (2 months on, 1 month off) demonstrated no significant difference in virologic or immunologic markers compared to continuous therapy, but did show increased development of drug resistance in the intermittent therapy arm (3 of 8 patients on efavirenz-based regimens developed NNRTI resistance).(283) Using STIs composed of shorter cycles (eg, 1 week on, 1 week off) or guided by CD4 count or viral load parameters, other investigators have shown that these types of intermittent therapy may be able to reduce drug toxicity, reduce time on drug, reduce cost, and improve quality of life without sacrificing clinical control of HIV.(284,285)

Two large trials have examined STI as a part of salvage therapy. In 1 study, highly treatment-experienced patients with advanced disease and drug-resistant virus were randomized to immediate salvage therapy versus salvage therapy following a 4-month treatment interruption.(286) That trial showed no benefit to the STI group, which in fact demonstrated a higher rate of AIDS-associated events, causing accrual to be closed early. In a second study, highly treatment-experienced patients were randomized to a 2-month STI versus no STI prior to initiating a 7- to 8-antiretroviral drug + hydroxyurea salvage regimen.(287) In this study, STI patients showed a benefit in viral load and CD4 cell response through 48 weeks. The disparate results in these trials are not easily reconciled. Differences in the patient population and duration of STI exist, but still fail to completely explain the differences in outcomes.

In general, studies of the safety and efficacy of STIs do not support their use in routine care, and STI cannot be recommended outside of a research setting.(35)

In a modification of this concept, the idea of partial treatment interruptions has emerged as a possibility for treating drug-resistant HIV.(288) In a small, selected cohort of patients with persistent viremia on a stable PI- and NRTI-containing antiretroviral regimen, discontinuation of the PI component of the regimen resulted in stable viremia, reduced toxicity, and halted accumulation of new PI mutations. Discontinuation of the NRTI component of the regimen, however, was associated with rapid rises in viral load.(274) This concept, too, must still be considered experimental and cannot be recommended for routine practice.

Control of HIV viremia depends on host immune response as well as exogenous intervention with antiretroviral medications. In an effort to enhance host immune response to HIV, several techniques of immune modulation have been studied. Early attempts at immune modulation through bone marrow transplantation, donor lymphocyte infusions, and cytokine infusions demonstrated no consistent, durable clinical benefit. Immunomodulatory approaches may prove more effective in combination with effective ART.

In the context of established infection, therapeutic immunization has been studied as a means to enhance HIV-specific immune responses. No study to date has demonstrated sustained clinical benefit to such "therapeutic vaccination." Some studies have demonstrated improved HIV-specific immune responses after therapeutic vaccination,(289) but the clinical significance of these responses remains unclear.

IL-2, a cytokine released by activated CD4 cells that regulates T-cell proliferation and maturation, has been studied as an immune modulator in HIV-infected patients. Administration of IL-2 to individuals with controlled HIV viremia leads to increased CD4 counts,(290-292) expansion of both memory and naive CD4 pools,(292) and decreased T-cell activation.(292) IL-2 administration is accompanied by numerous adverse effects and toxicities. No clinical benefits of IL-2 have yet been demonstrated. Large clinical trials of IL-2 are underway. Other cytokines, such as IL-12 (293) and IL-4 (294) are being studied, as is IL-2 in combination with therapeutic vaccination.

Techniques of immune manipulation through infusion of antigen-presenting cells that have been activated in vitro,(295) infusion of expanded (296) or activated (297) CD4 cells, and genetic manipulation of cells to induce anti-HIV CTL activity (298) are also under investigation, but even if such resource-intensive, individualized approaches are shown to be effective, it is doubtful that they will become accessible to most people infected with HIV.

Administration of human growth hormone (hGH) as a method of enhancing CD4 recovery in HIV is another technique being studied, spurred by the observations of increased circulating naive CD4 cells and increased thymic mass, suggesting increased thymopoeisis, during hGH treatment.(299)

Many commonly encountered OIs may be prevented by administering prophylactic antibiotics to those at risk, based on pathogen-specific CD4 cell count thresholds.(207) In geographic areas where local epidemiology of opportunistic pathogens varies from that of the United States, different recommendations for primary prophylaxis (treatment to prevent an initial episode of an OI) may be appropriate. In general, secondary prophylaxis (treatment to prevent recurrence of an OI) should be provided as long as immune impairment persists.

Among individuals who experience reconstitution of immunologic function with ART, as assessed by sustained increases in CD4 count to levels above those associated with OI, discontinuation of primary prophylaxis or secondary prophylaxis has been shown to be safe.(300)

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