HIV, in common with other retroviruses, possesses the enzyme reverse transcriptase and consists of a lipid bilayer membrane surrounding the capsid (Fig. 41.1). Its surface glycoprotein molecule (gp120) has a strong affinity for the CD4 receptor protein found predominantly on the T-helper/inducer lymphocytes. Monocytes and macrophages may also possess CD4 receptors in low densities and can therefore also be infected. The process of HIV entry is more complex than originally thought, and in addition to CD4 attachment, subsequent binding to co-receptors such as CCR-5 or CXCR-4 and membrane fusion also occur (Fig. 41.2).

Fig. 41.1 Structure of the human immunodeficiency virus (HIV).

Fig. 41.2 Lifecycle of HIV and the sites of action of currently available antiretroviral agents (in bold).

After penetrating the host cell, the virus sheds its outer coat and releases its genetic material. Using the reverse transcriptase enzyme, the viral RNA is converted to DNA using nucleosides. The viral DNA is then integrated into the host genome in the cell nucleus, where it undergoes transcription and translation, enabling the production of new viral proteins. New virus particles are then assembled and bud out of the host cell, finally maturing into infectious virions under the influence of the protease enzyme.

Immediately after primary HIV Infection (PHI, also known as ‘seroconversion’), there is a very high rate of viral turnover. Equilibrium is then reached, at which stage the infection may appear to be clinically latent, but in fact, as many as 10,000 million new virions are produced each day.

Over time, as chronic infection ensues, cells possessing CD4 receptors, particularly the T-helper lymphocytes, are depleted from the body. The T-helper cell is often considered to be the conductor of the ‘immune orchestra’ and thus, as this cell is depleted, the individual becomes susceptible to a myriad of infections and tumours. The rate at which this immunosuppression progresses is variable and the precise interaction of factors affecting it is still not fully understood. It is well recognised that some individuals rapidly develop severe immunosuppression, whilst others may have been infected with HIV for many years whilst maintaining a relatively intact immune system. It is likely that a combination of viral, host (genetic) and environmental factors contributes to this variation.

Clinical manifestations

The sequelae of untreated HIV infection can be broadly considered in five categories:

• Opportunistic infections, that is, infections that would not normally cause disease in an immunocompetent host, for example, P. jiroveci pneumonia and cytomegalovirus (CMV)

• Infections that can occur in immunocompetent patients but tend to occur more frequently, more severely and often atypically in the context of underlying HIV infection, for example, Salmonella, herpes simplex and Mycobacterium tuberculosis

• Malignancies, particularly those that occur rarely in the immunocompetent population, for example, Kaposi’s sarcoma and non-Hodgkin’s lymphoma

• Direct manifestations of HIV infection per se, for example, HIV encephalopathy, HIV myelopathy and HIV enteropathy

• Consequences of chronic immune activation including premature cardiovascular disease, neurocognitive dysfunction, bone mineral density loss.

In addition, approximately 70% of individuals develop a flu-like illness at seroconversion. This primary HIV infection (PHI) is characterised by fever, arthralgia, pharyngitis, rash and lymphadenopathy. Rarely, the degree of associated CD4 count depletion may be sufficient to result in development of an opportunistic illness such as oropharyngeal/oesophageal candidiasis or P. jiroveci pneumonia.

Opportunistic infections generally fall into two categories:

• DNA viruses, for example, CMV and JC virus

• Intracellular pathogens, for example, P. jiroveci, Toxoplasma gondii and Mycobacterium avium.

Although the clinical course of HIV disease varies with each individual, there is a fairly consistent and predictable pattern that enables appropriate interventions and preventive measures to be adopted. Patients can be classified into one of three groups according to their clinical status: asymptomatic, symptomatic or AIDS. Symptomatic disease is characterised by non-specific symptomatology such as fevers, night sweats, lethargy and weight loss, or by complications including oral candidiasis, oral hairy leucoplakia, and recurrent herpes simplex or herpes zoster infections. AIDS is defined by the diagnosis of one or more specific conditions including P. jiroveci pneumonia, M. tuberculosis infection and CMV disease.

Investigations and monitoring

Current and previous infections

The initial diagnosis of HIV infection is made by the detection of antibodies against HIV. With improved technology, it is usually possible to detect antibodies within 3–4 weeks of infection, although individuals are advised that a ‘window period’ of up to 3 months after exposure is required before infection can be excluded. After confirmation of HIV infection, the patient is usually tested for prior exposure to a number of potential pathogens, including syphilis, hepatitis A, B and C, CMV, varicella zoster (VZV), and T. gondii. This can enable subsequent treatment (in the case of undiagnosed syphilis), vaccination (if no prior exposure to hepatitis A, B, or VZV), prevention (if no prior exposure to Toxoplasma and CMV), prophylaxis (if previous exposure to Toxoplasma) and can aid subsequent diagnosis (according to CMV or Toxoplasma status).

CD4 count

The level of immunosuppression is most easily estimated by monitoring a patient’s CD4 count. This measures the number of CD4-positive T-lymphocytes in a sample of peripheral blood. The normal range can vary between 500 and 1500 cells/mm³. As HIV disease progresses, the number of cells falls. Particular complications of HIV infection usually begin to occur at similar CD4 counts (Fig. 41.3) which can assist in differential diagnoses and enable the use of prophylactic therapies. For example, patients with a CD4 count of less than 200 cells/mm³ should always be offered prophylaxis against P. jiroveci pneumonia. Similarly, both patient and clinician are likely to use the CD4 count as the major indicator of when to consider starting antiretroviral therapy.

Fig. 41.3 Opportunistic complications of HIV infection and the CD4 count ranges at which they commonly occur.

Viral load

The measurement of plasma HIV RNA (viral load) estimates the amount of circulating virus in the blood. This has been proven to correlate with prognosis, with a high viral load predicting faster disease progression (Mellors et al., 1997). Conversely, a reduction in viral load after commencement of antiviral therapy is associated with clinical benefit. This measure, in combination with the CD4 count, allows patients and clinicians to make informed decisions regarding when to start and when to change antiviral therapies, enabling the more effective use of such agents. There are on-line calculators utilising viral load and CD4 count to model risk of disease progression or death based on large cohort studies.

Resistance testing

Due to the implications of transmitted (primary) resistance, it is recommended that all patients have a genotypic HIV resistance test performed soon after diagnosis; this will ensure that appropriate initial therapy is selected. Further resistance tests should be performed at any subsequent virological failure to direct therapy choice.

Tropism testing

Viruses may enter the cell using the CCR5 co-receptor, the CXCR4 co-receptor or both co-receptors. Those which just use one co-receptor are known as CCR5-tropic or CXCR4-tropic viruses; those which can use both receptor types are called dual-tropic. Where a mixture of virus populations is present, the term mixed-tropic is used. Different methods of determining tropism are currently under evaluation. The tests must be performed in real time as viral tropism changes as the disease progresses. If CCR5 inhibitors are to be used, it is essential to determine that the virus is CCR5-tropic, that is, that there is no significant use of the CXCR4 receptor.

Drug treatment

The drug treatment of HIV disease can be classified as antiretroviral therapy, the management of opportunistic infections or malignancies, the management of ‘non-HIV-related’ co-morbidities, and symptom control. For the first decade of the epidemic, most of the available drugs and therapeutic strategies were aimed at treating or preventing opportunistic complications and alleviating HIV-related symptoms. Whilst these are still important, there has been a shift in emphasis towards treatment aimed at reducing the HIV viral load, restoring immune function and reducing the potential consequences of co-morbidities.

Due to the speed at which new antiretroviral agents are being developed, comprehensive data on drug interactions, side effects, etc., are often lacking. Thus, the ability to apply general pharmacological and pharmacokinetic principles, together with common sense, is required.

The treatment of many of the opportunistic complications of HIV comprises an induction phase of high-dose therapy, followed by maintenance and/or secondary prophylaxis using lower doses. This is due to the high rate of relapse or progression after a first episode of diseases such as P. jiroveci pneumonia, cerebral toxoplasmosis (toxoplasmic encephalitis), systemic cryptococcosis and CMV retinitis. Where a cost-effective agent with an acceptable risk/benefit ratio exists, primary prophylaxis may be offered to individuals who are deemed to be at high risk of developing a particular opportunistic infection, for example, P. jiroveci pneumonia prophylaxis. Discontinuation of prophylaxis, both primary and secondary, is now usually possible in individuals who demonstrate immunological restoration on Highly Active Antiretroviral Therapy (HAART).

Paradoxically, this immunological restoration may result in apparent clinical deterioration with opportunistic infections during the first few weeks after initiation of HAART. This is known as immune reconstitution inflammatory syndrome (IRIS).

The goals of therapy in HIV-positive individuals are to:

• improve the quality and duration of life;

• prevent deterioration of immune function and/or restore immune status;

• treat and/or prevent opportunistic infections;

• relieve symptoms.

Antiretroviral therapy

Antiretroviral therapy is currently one of the fastest evolving areas of medicine. The specific details of treatment will therefore continue to change as new drugs emerge, although it is likely that the following general principles will remain:

• A combination of three antiretroviral agents, selected on the basis of treatment history and resistance tests, should usually be prescribed to increase efficacy and reduce the development of drug-resistant virus

• Wherever possible, a regimen should contain at least one drug that penetrates the central nervous system and confers protection against HIV-related encephalopathy/dementia

• Treatment strategies should be adopted that sequence drug combinations, being mindful of potential cross-resistance and future therapy options

• Given the crucial importance of a high level of adherence to these therapies, the regimen adopted for a particular individual should, wherever possible, be tailored to suit the daily lifestyle.

Many organisations, such as the British HIV Association (BHIVA), the European AIDS Clinical Society (EACS) and the International AIDS Society (IAS), produce regularly updated guidelines on the use of antiretroviral therapy, for example, Gazzard et al. (2008). These guidelines include the most up-to-date considerations of:

• when to start therapy;

• what to start with;

• how to monitor, including use of therapeutic drug monitoring and resistance testing;

• when to switch therapy;

• what therapy to switch to;

• treating individuals who have been highly exposed to multiple agents;

• managing individuals with significant co-morbidities, for example, tuberculosis or hepatitis B/C.

Most studies evaluating triple combinations of antiretrovirals have been designed with so-called surrogate marker endpoints, measuring the effect on laboratory parameters such as CD4 count and HIV viral load. These trials are generally smaller and shorter in duration than clinical endpoint studies that are powered to measure the impact on survival and disease progression. The first large clinical endpoint trial that demonstrated the superiority of a triple combination over dual therapy was undertaken by Hammer et al. (1997). Following the results of this trial, the standard approach, where treatment is indicated, has been to use a combination of at least three agents. The reduction in morbidity and mortality associated with HAART has been confirmed in routine clinical practice, as well as in other trials (e.g. Palella et al., 1998; Smit et al., 2006). Subsequent clinical trials have largely been for licensing purposes and/or have served to refine therapeutic choices rather than to change the paradigm of treatment. The concept of intermittent rather than continuous therapy was evaluated in the SMART study but shown to be linked with an increased risk of co-morbidities not previously thought to be associated with HIV (such as cardiovascular disease, hepatic and renal failure) as well as HIV disease progression (El-Sadr et al., 2006). The use of protease inhibitor (PI) ‘monotherapy’ compared to conventional triple therapy has been evaluated in a number of small studies, for example, Arribas et al. (2009), and is being investigated in longer-term strategic studies. A large international study of early versus deferred treatment, to attempt to address the question of when to initiate treatment, is ongoing.

When to start therapy

Current UK guidelines recommend starting antiretrovirals when the CD4 count drops below 350 cells/mm³. Therapy should be considered at a higher CD4 count in specific situations, for example, in the presence of an AIDS-defining illness or HIV-related morbidity.

Choosing and monitoring therapy

The majority of individuals are currently commenced on a combination of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) or two NRTIs and a boosted PI. The term ‘boosted PI’ refers to a combination of one PI combined with a low dose (usually 100–200 mg once or twice daily) of ritonavir, another PI. The ritonavir does not directly add to the antiretroviral activity of the regimen; it is used purely as a pharmacokinetic enhancer of the other PI, by increasing the maximum plasma concentration, C_max, due to inhibition of cytochrome P450 enzymes in the gut wall and/or extending the half-life, t_1/2, by inhibition of hepatic cytochrome P450 enzymes. Triple NRTI therapy is no longer recommended, as it is associated with unacceptable rates of virological failure. Alternative strategies, such as NRTI-sparing regimens and boosted PI monotherapy, are currently only routinely recommended in a research setting. More recently, integrase inhibitors have been approved for initial therapy and may be used as an alternative to NNRTIs or PIs.

The aim of initial therapy is to achieve viral load suppression in the plasma to levels below the detection limits of available assays (40 or 50 copies/mL). Such virological suppression is almost invariably accompanied by an elevation in CD4 count and clinical evidence of immune reconstitution. Whilst sustained suppression over many years is usually possible, viral rebound may occur and is often accompanied by the development of resistance to one or more agents in the combination. Upon confirmed virological failure, a resistance test is performed which will help to identify to which agents the virus may have adapted and the extent to which any such resistance mutations may confer cross-resistance to other available drugs. A second-line regimen is then constructed, wherever possible utilising a new class of drug to which the individual has not previously been exposed. Upon virological failure of subsequent regimens, the therapeutic options available become increasingly complex, but with the availability of more agents targeting different parts of the virus life cycle, virological suppression is still usually possible and should remain the goal of treatment.

Many of the antiretrovirals, particularly the PIs and NNRTIs, exhibit a wide range of interactions, especially with other drugs that are metabolised by the cytochrome P450 enzyme system, including prescribed, ‘over-the-counter’, herbal and recreational drugs. HAART failure (detectable viral load and drug resistance) has been documented following co-administration of hepatic enzyme inducers, including non-prescribed agents such as St John’s Wort. Conversely, serious and even fatal toxicities due to enzyme inhibition by the PIs continue to be reported. These include Cushing’s syndrome following concomitant use of fluticasone or budesonide inhaler or nasal spray with a PI. This highlights the necessity of taking a comprehensive drug history prior to starting or switching HAART and ensuring patients and prescribers are aware of the need to check the interaction potential of new medicines. General prescribing guidelines for antiretrovirals are presented in Box 41.1 whilst details of common side effects and interactions of the currently available agents are summarised in Tables 41.1 to 41.5.

Box 41.1 General prescribing and monitoring information for antiretroviral agents

• The Summary of Product Characteristics, current British National Formulary (BNF) and national guidelines should be consulted when managing the treatment of an HIV-positive patient.

• Adverse events should be reported. With greater exposure and long-term use, it is likely that more adverse events will be recognised. Some of these may be class effects associated with particular groups of antiretrovirals and should therefore be monitored even in new agents within a class. Examples include dyslipidaemia and diabetes mellitus with protease inhibitors, mitochondrial myopathy and lipoatrophy with NRTIs, rash with NNRTIs.

• There are limited data on the safety of many antiretroviral drugs when taken during pregnancy, or their long-term effects on babies/children. Updated safety information from the Antiretroviral Pregnancy Register is published twice yearly. Efavirenz has been shown to be teratogenic in animal studies, but comparable data are not available for the other antiretrovirals. Caution should therefore be exercised with all agents. Treatment of women who are planning conception or who are pregnant must be discussed with the relevant experts. All pregnant women who are treated with antiretrovirals should be reported prospectively to the Antiretroviral Pregnancy Register.

Table 41.1 General prescribing points for nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs)

Table 41.2 General prescribing points for non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Table 41.3 General prescribing points for protease inhibitors

Table 41.4 General prescribing points for Integrase Inhibitors

Table 41.5 General prescribing points for entry inhibitors

The routine use of therapeutic drug monitoring is not recommended but blood levels of PIs and NNRTIs should be measured in selected patients, for example, during pregnancy, where there is liver impairment and where there are concerns regarding potentially interacting drugs (Gazzard et al., 2008).

HIV mutates readily and resistance to some antiretrovirals, particularly reverse transcriptase inhibitors and integrase inhibitors, develops rapidly in the face of suboptimal treatment, for example, monotherapy or subtherapeutic blood levels. A high level of adherence to treatment is crucial to the sustained, successful outcome of antiretroviral regimens and has been the subject of much research. For example, in one study of people taking their first regimen containing nelfinavir, it was found that at least 95% adherence was required to achieve a sustained response in the majority (78%) of patients. The chances of treatment success declined as the level of adherence dropped, such that 80% of patients whose adherence was below 80% experienced virological failure. Virological success was also found to correlate with a better clinical outcome in terms of fewer hospitalisations, opportunistic infections and deaths (Paterson et al., 2000). Such clinical trial data have also been supported by clinical experience in the UK and elsewhere, although it has yet to be established if the level of adherence required is the same for all regimens and every patient. In view of this, patients should be advised to take HAART as close as possible to the same time every day and certainly within 1 hour of the agreed time each day. If they forget a dose, it should be taken as soon as they remember and then return to the original schedule.

There has been significant progress over recent years in reducing some of the physical burden of therapy, through the development of combination tablets and the use of strategies such as ritonavir boosting to reduce dietary restrictions and dosing frequency. Adherence aids such as pill boxes, medication record cards and alarms (e.g. on mobile phone) can also help to support adherence. However, practical issues are not the only barriers to adherence and the individual’s health beliefs and motivation, particularly around HIV and antiretroviral therapy, should also be addressed before treatment is commenced, as these are likely to have a significant impact on outcome (Horne et al., 2004). Although there is little evidence to demonstrate what the optimal interventions to improve adherence are, multidisciplinary and multiagency approaches appear to be most useful (Poppa et al., 2003).

Treatment interruptions

For many reasons, including toxicity, cost and adherence, patients and clinicians have been interested in considering ‘drug holidays’ or treatment interruptions. However, this strategy is no longer recommended in routine practice (El-Sadr et al., 2006). It is now recognised that there are dangers associated with this approach because of CD4 decline, disease progression, mortality related to co-morbidities, for example, cardiovascular disease, and viral load rebound associated with increased transmission risk and a seroconversion-like syndrome. Further, as different anti-HIV medications have different half-lives, there may be a risk of functional monotherapy, particularly with NNRTIs, and the development of resistance if combinations are stopped abruptly in an unplanned fashion.

Post-exposure prophylaxis

Post-exposure prophylaxis (PEP) involves the use of antiretroviral drugs to prevent infection with HIV after possible exposure, which may be recommended after occupational injuries (DH, 2008) or sexual exposure (Fisher et al., 2006). Whilst PEP is a largely unproven and unlicensed indication for the drugs used, it is supported by animal model data and case–control studies. Where recommended in guidelines, PEP is usually commenced as a 3–5-day starter regimen of two NRTIs and a boosted PI, followed by an ongoing course for a total of 4-week post-exposure. It is believed this will reduce the likelihood of infection by at least 80%, although toxicity issues are not insignificant. Therefore, the decision to prescribe or take PEP must reflect a careful risk/benefit evaluation. Studies of pre-exposure prophylaxis (PREP), using one or two antiretrovirals (orally or topically) before potential exposure to HIV, have so far yielded mixed results, but may offer additional options to reduce transmission.