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Ovid: Oxford Handbook of Genitourinary Medicine, HIV, and Aids

Editors: Pattman, Richard; Snow, Michael; Handy, Pauline; Sankar, K. Nathan; Elawad, Babiker Title: Oxford Handbook of Genitourinary Medicine, HIV, and Aids, 1st Edition Copyright ©2005 Oxford University Press > Table of Contents > HIV/AIDS > Chapter 53 – HIV: management Chapter 53 HIV: management P.510
Introduction Highly active antiretroviral therapy (HAART) has produced dramatic improvements in the prognosis of HIV infection with ↓ rates of mortality and opportunist infections (OIs). Important principles to consider in those under regular review are:

  • treat before symptomatic disease or critical immunological damage;
  • avoid treating earlier than necessary to ↓ long term drug side-effects;
  • regimen choice must consider patient lifestyle, potential drug interactions, and side-effects while ensuring adequate antiviral potency.

Patient’s commitment to starting treatment is essential. Pre-treatment adherence education is vital as adherence must be >95% to obtain both maximum magnitude and duration of antiviral effect. HAART rarely needs starting as an emergency. Drug resistance should be assayed pre-treatment, ideally at diagnosis, because of possible resistant viral transmission. When to start Primary infection Prime indication for treatment is severe symptoms (which may indicate risk of more rapid progression to symptomatic disease). These may resolve with HAART. Treatment duration is undefined and its influence on subsequent clinical course is uncertain. Chronic infection In the asymptomatic patient, the likelihood of developing clinical AIDS over a 3 year period can be predicted from a combination of viral load (VL) and CD4 count (see Fig. 53.1). CD4 counts give the best indication of OI risk but high VLs are associated with more rapid rates of CD4 ↓. HAART should be offered:

  • if HIV-related symptoms (independent of VL and CD4 count) are observed
  • before CD4 counts have fallen <200cells/µL (if asymptomatic). The point of maximal ‘cost-effectiveness’ has not been defined by trial data but the consensus is that treatment should be commenced with CD4 counts 200–350cells/µL depending on:
    • rapidity of CD4 ↓
    • VL levelit
    • patient preference.

Other factors e.g. older age (↑ speed of development immunodeficiency) should also be considered. In pregnancy, treatment may be given to ↓ risk of mother to child transmission when such therapy may not be indicated in the non-pregnant state. Starting HAART at very low CD4 counts ↑ drug side-effects although with nevirapine hepatotoxicity is ↑ by CD4 counts >250cells/µL. In patients with active OIs commencement of HAART should be deferred if P.511
possible until after completion/simplification of treatment for the OI, particularly tuberculosis (TB) as major drug interactions may occur. Once started, treatment (except when given for fetal protection) should be continued indefinitely.

Fig. 53.1 Prognosis according to CD4 cell count and viral load in the pre-HAART and HAART eras. Source: Reprinted with permission from Elsevier (Egger M et al., Lancet 2002, 360, 119–29).

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How to start Initial treatment influences the pattern of resistance mutations. If it fails, the range of drugs available for 2nd line therapy is restricted. Therefore the following are important aims of the first treatment.

  • Maximize adherence—especially important for regimens containing drugs where resistance may be produced by single mutations (e.g. lamivudine and NNRTIs).Treatment based on a ↓ CD4 count should be continued long term. Intermittent therapy should only be considered in those achieving full viral suppression. For fully informed patients insisting on this option the interruption of long half-life drugs needs special care. If efavirenz is involved NRTI backbone should be continued for 2 weeks at least after efavirenz cessation with or without a PI.
  • Minimize drug reactions.
  • Include drugs with good penetration to the central nervous system.
  • Avoid toxicity/interaction. Toxicity of some antiretroviral drugs (e.g. stavudine causing lipodystrophy) makes them unsuitable as 1st line therapy. Drug combinations with additive toxicity (e.g. didanosine + stavudine) and shared intracellular activation pathways (e.g. zidovudine and stavudine) should be avoided (see p. 517).

Drug combinations in the treatment naïve should take account of resistance testing, co-pathologies, risk factors for diabetes and cardiovascular disease, lifestyle, and informed patient choice. Adherence Essential for successful viral suppression. Stress importance prior to starting treatment and continually reinforce as adherence may diminish with time. Sub-therapeutic drug levels select for HIV resistant mutations arising from error-prone viral replication. Some regimens have low genetic barrier to resistance. Investing in strategies that improve adherence is more cost effective than managing the consequences of poor compliance. Such strategies will also minimize the risk of transmission of drug-resistant virus which may adversely affect HAART response in the newly infected. Factors influencing adherence

  • Patient
    • Commitmentit
    • Religious/cultural/health beliefsit
    • Poor diet (may be related to socio-economic difficulties)
    • Need to take medication (seen by family/workmates)
    • Drug and alcohol useit
    • Psychological (depression associated with low adherence)
    • Presence of symptoms/side-effects (may encourage/discourage adherence, respectively)
    • Relationship with healthcare team.
  • P.513

  • Provider
    • Provision of adherence support services
    • Patient education.
  • Regimen
    • Lifestyle assessment and compliance with regimen
    • Dosing frequency, pill burden, and food/fluid requirements.

How to improve adherence Multi-factorial approach should be adopted, taking account of the patient’s perceptions of the benefits as well as the practicalities of treatment. The individual’s commitment to taking drugs should be assessed before starting therapy and at regular intervals. Concerns about drug side-effects should be explored. Motivational techniques can help patients strengthen their intentions and adherence behaviour. Psychosocial aspects including relationships, alcohol and drug use, housing, employment, and immigration status should be considered, with appropriate professional involvement. Measures that may improve adherence:

  • programmable wristwatches, text messaging, telephone reminders, pill diaries and charts, medication containers, and help of family and friends;
  • input from nurses, health advisers, psychologists, and pharmacists;
  • written information.

There is no ideal and accurate method to monitor adherence. Self-reporting, pill counting, self-completed questionnaires, and drug levels have all been used with varying success. P.514
What to start with Current classes of antiretroviral drugs inhibit the virus at different stages of its cellular lifecycle (see Fig. 53.2):

  • interaction with CD4/chemokine receptors—fusion inhibitors
  • inhibition of reverse transcription (conversion of viral RNA to pro-viral DNA)
    • nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
    • non-nucleoside reverse transcriptase inhibitors (NNRTIs)
    • inhibition of protease processing of viral sub-units leading to assembly of infective virions—protease inhibitors (PIs).

Other therapeutic targets in the viral lifecycle are under investigation. Combination treatment Triple combinations are the standard of care. The drug, classes have differing side-effects, drug interactions, and impact on co-pathologies. Individual drugs, within classes, may have significantly better convenience, tolerability, or side-effect profiles than others e.g. atazanavir (PI)—↓ effect on lipids and once a day therapy. Standard regimens for both asymptomatic and late diseases

  • 2 NRTIs (beware inadvisable combinations—see p. 517) plus a NNRTI;
  • 2 NRTIs plus a PI (usually boosted with low dose ritonavir);
  • Triple nucleoside analogue combinations (e.g. Trizivir®). Lack potency at high (>100,000copies/mL) VLs but have the advantages of simplicity and ↓ risks of drug interactions (useful in patients requiring simultaneous treatment for TB). Initial therapy should be restricted to patients with special adherence or drug interaction problems.
  NNRTI PI
Advantages
  1. Low pill burden
  2. ↓lipid abnormalities/central fat accumulation
  3. Once daily doage possible
  1. ↓skin rash/hepatotoxicity
  2. ↓broad class resistance
  3. High barrier to genetic resistance e.g. Kaletra®
Disadvantages
  1. Class resistance with single mutations
  2. Ineffective against HIV-2 (inherent resistance)
  1. Heavy pill burden (most)
  2. Hyperlipidaemia, insulin resistance, lipodystrophy, central fat distribution if predisposed
  3. ↑ drug interactions
  4. ↑ food/fluid requirements/ restrictions especially when unboosted

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Currently most treatment naïve patients are started on NNRTI regimens. Efavirenz and nevirapine have different side-effect profiles but are of equivalent potency. Nevirapine is associated with skin rash and hepatic reactions and efavirenz, neuropsychological side-effects and potential teratogenicity.

Fig. 53.2 HIV lifecycle and points of drug action

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NRTIs (nucleotide—tenofovir). All oral

Abacavir* (ABC) 300mg bd Hypersensitivity (may be fatal) in 4%: fever, malaise, rash, GI.
Do not rechallenge.
Didanosine (DDI) 400mg if >60kg (or 300mg) daily Take on empty stomach. Peripheral neuropathy, pancreatitis, nausea, diarrhoea. Rarely lactic acidosis, hepatic steatosis.
Emtricitabine (FTC) 200mg daily Minimal. Rarely lactic acidosis, hepatic steatosis.
Lamivudine* (3TC) 150mg bd or 300mg daily† Minimal. Rarely lactic acidosis, hepatic steatosis.
Stavudine* (D4T) 40mg if >60kg (or 30mg) bd Peripheral neuropathy, lipodystrophy, pancreatitis, lactic acidosis, hepatic steatosis.
Zalcitabine (DDC) 0.75mg tid Peripheral neuropathy, stomatitis, pancreatitis, lactic acidosis, hepatic steatosis.
Zidovudine* (AZT) 250–300mg bd Bone marrow suppression (anaemia, neutropenia), myopathy. Rarely lactic acidosis, hepatic steatosis.
Tenofovir (TDF) 300mg daily Asthenia, headache, GI, rarely renal insufficiency.
* Consistent CSF penetration.
† Reduce to 250mg when combined with TDF.

NRTI combined preparations

Combivir® 1 tablet bd, contains AZT 300mg + 3TC 150mg.
Trizivir® 1 tablet bd, contains AZT 300mg + 3TC 150mg + ABC 300mg.
Truvada® 1 tablet daily, contains TDF 300mg and FTC 200mg.
Kivexa®/Epzicom® 1 tablet daily contains ABC 600mg and 3TC 300mg.

NNRTIs. All oral and show evidence of consistent CSF penetration

Efavirenz (EFZ) 600mg daily CNS effects (advise take at night), hepatitis, contra-indicated in pregnancy.
Nevirapine (NVP) 200mg bd or 400mg/day Initially 200mg/day ↑ to 400mg/day after 2/52 Rash, Stevens–Johnson syndrome, hepatitis.
Delavirdine (DLV) 400mg tid Diarrhoea, itching, and rashNot routinely available in the UK.

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Boosted PI dosages with ritonavir (RTV), 100mg bd (except Kaletra® which already includes RTV) or 100mg daily with ATZ. All oral. When boosted, food restrictions are not critical. Only indinavir shows evidence of consistent CSF penetration

Amprenavir (APV) 600mg (if >50kg) bd GI, rash, oral pararthesia, lipodystrophy.
Atazanavir (ATZ) 300mg daily Indirect hyperbilirubinaemia, cardiac conduction defect (prolonged PR interval).
Fosamprenavir (FPV) 700mg bd GI, rash, lipodystrophy (less than other PIs).
Indinavir (IDV) 800mg bd Nephrolithiasis, GI, indirect hyperbilirubinaemia lipodystrophy. ↑fluids by 2L.
Kaletra® 3 capsules bd GI, ↑ transaminases, asthenia, lipodystrophy.
Lopinavir (LPV) 133.3mg + RTV 33.3mg    
Saquinavir tabs 1.0g bd GI, headache, ↑ transaminase, lipodystrophy.

PIs used without additional PI boosting. Both oral

Nelfinavir (NFV) 1.25g bd Take with food Diarrhoea, ↑ transaminase, lipodystrophy.
Ritonavir (RTV) 600mg bd Take with food GI, parasthesia, hepatitis, raised transaminase, pancreatitis, lipodystrophy.

Fusion inhibitor (FI). Licensed for treatment failure. Subcutaneous administration

Enfuvirtide (ENF) 90mg bd Injection site reaction, ↑ pneumonia, hypersensitivity reaction (may recur on re-challenge).

Antiretroviral drug combinations to avoid

  • D4T+AZT—thymidine analogues compete for the same intracellular enzyme plus antagonistic effect;
  • FTC+3TC—cytosine analogues—no additive activity;
  • ABC+3TC+TDF—↑ virological failure.
  • DDI + TDF + EFZ—↑ virological failure in treatment naive patients.

Caution with

  • DDI and D4T—↑ peripheral neuropathy, lactic acidosis, and acute pancreatitis, especially in pregnancy;
  • DDC+DDI—↑ peripheral neuropathy;
  • DDC+D4T—↑ peripheral neuropathy.

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Monitoring therapy Side-effects are very common with HAART although most spontaneously resolve after a few weeks. Patients should be asked to report side-effects and be given written information about serious complications e.g. abacavir hypersensitivity reactions. Consideration should be given to providing anti-emetics and anti-diarrhoeal agents for the common early gastrointestinal symptoms. Sedatives may be needed for severe EFZ associated insomnia/vivid dreams. Routine tests

  • Full blood count, liver function (LFTs)/renal function tests—should be checked 2 weeks into treatment and then at subsequent clinic visits. Patients who develop abnormal LFTs or a significant anion gap should have plasma lactate level checked.
  • VL—the rate of fall on therapy is a useful prognostic indicator. Whatever the pre-treatment VL, suppression to a level of 1,000copies/mL or less is achievable in most patients by 4 weeks. When not attained associated with longer term failure. The success of a treatment combination can be judged by achieving a VL of <50copies/mL within 3–6 months, then maintained for 48 weeks.
  • CD4 count—usually ↑ with viral suppression initially as a result of re-circulated existing reserves. Further ↑ and maintenance of continuous production of CD4 cells dependant on ability of thymus to produce new T cells. Complete restoration does not occur in most chronically infected patients but immune reconstitution occurs to varying degrees even in those who achieve limited viral suppression. Prophylaxis against PCP can be discontinued in those responding to therapy (CD4 count >200cells/µL for at least 3–6 months).

Both CD4 and VL should be checked and repeated at 4 weeks and 12 weeks into therapy and then at 3 monthly intervals if virological control is achieved.

  • Lipid profiles—should be checked 3 monthly and major abnormalities addressed. Monitor for the development of lipodystrophy and consider early treatment switches if apparent. Elevated random lipids should be re-measured while fasting.
  • Blood sugar levels—should be monitored, particularly with PI therapy. Fasting blood sugar should be measured if random level elevated.

Adherence reinforcement should be undertaken at each visit. Risk of acquisition of co-infections and STIs should be assessed and tested for when appropriate. P.519
Therapeutic drug monitoring (TDM) Up to 35% of patients taking PIs have sub-optimal drug concentrations with ~50% developing virological failure. A fixed drug dose may not be appropriate for all patients. Measuring drug levels to determine therapeutic dose may help promote durable viral suppression and ↓ resistance. Dose–response and concentration–response relationships have been identified for PIs and NNRTIs (some data for NRTIs). Potential use of TDM Only of value if highly adherent (>95%) and at steady-state conditions (after at least 14 days of therapy). Blood samples should be obtained at the end of the dosing interval, as close to minimum concentration (Cmin) as possible, to enable comparison with product monograph concentrations. TDM can be of benefit in:

  • pregnant ♀ and children—may have altered/highly variable pharmacokinetics;
  • highly adherent individuals who have poor initial or transient viral responses not explained by viral resistance. In these situations Cmin values may assist in assessing genetically determined high hepatic metabolic rates, poor absorption, or drug interactions that prevent adequate drug levels. Adjusting antiretroviral doses to achieve Cmin values within 30% of the mean/median value of the product monograph may ↑ likelihood of adequate therapeutic levels and viral response;
  • those on new drug therapy with unknown/potential drug interactions;
  • those on once daily PI—ensures adequate 24 hour drug concentration.

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Major drug side-effects and interactions Mitochondrial toxicity A mechanism by which NRTIs may cause myopathy, peripheral neuropathy, hepatic steatosis, lactic acidosis, and, in infants, neurological disease. However, the link is strongest with lactic acidosis. This has been reported in infants born to mothers receiving AZT or 3TC+AZT. D4T+DDI has been associated with lactic acidosis in pregnancy and should be avoided/switched. Caused by inhibition of mitochondrial γ DNA polymerase, the enzyme responsible for DNA synthesis, but effects on other mitochondrial enzymes may contribute. D4T, DDC, and DDI inhibit γ DNA polymerase whereas AZT inhibits other mitochondrial enzymes. Hence toxicity induced by D4T improves on switching to AZT or ABC. Hyperlactataemia Clinical significance of isolated hyperlactataemia (venous lactate between 2.5 and 5.0mmol/L) unknown. Routine measurement of venous lactate and anion gap in asymptomatic patients not recommended. Lactic acidosis Characterized by arterial pH <7.35 and venous lactate >5mmol/L (sample taken without tourniquet into tube containing fluoride-oxalate, transported immediately on ice to laboratory). Occurs most frequently with D4T and in ♀. Usually develops after several months of treatment. Main features are nausea, vomiting, weight loss, fatigue, abdominal pain, tender hepatomegaly, and respiratory failure. Laboratory findings:

  • venous lactate >5.0mmol/L, metabolic acidosis, high anion gap (usually >18mmol/L);
  • ultrasound and CT abdomen—hepatomegaly with fatty infiltration (microvascular steatosis found on liver biopsy);
  • may find—↑ hepatic transaminases, creatine kinase, lactate dehydrogenase, and amylase.

Management Diagnosis must be considered in any patient presenting with nausea, vomiting, abdominal pain, and abnormal LFTs. Essential to discontinue antiretroviral medication and to exclude other causes. Supportive therapy required with fluid replacement, oxygen therapy and, if necessary, assisted ventilation and haemodialysis. Benefit from carnitine, thiamine, co-enzyme Q, and riboflavin is limited. Peripheral neuropathy Risk of drug induced peripheral neuropathy ↑ with HIV disease progression. Reported with NRTIs, more frequent with DDC, D4T, and DDI. Presents with distal symmetric polyneuropathy (DSP), which may be difficult to differentiate from HIV-related DSP but tends to be painful, more sudden and progressive. Discontinuation of the offending NRTI may result in improvement but symptoms may deteriorate for several weeks. Pain relief may be obtained with acetyl-L-carnitine, tricyclic antidepressants, anticonvulsants (gabapentin and lamotrigine), and recombinant human nerve growth factor. P.521
Important antiretroviral interactions with other drugs

Drug ART Effect Action
Terfenadine All PIs and NNRTIs Dangerous arrhythmias Use loratidine or cetirizine
Midazolam and triazolam All PIs and EFZ Increased sedating effect Use alternative sedative
Rifampicin All PIs and NNRTIs Complex effect on cytochrome P450 Use rifabutin instead
Rifabutin SQV ↓ SQV by 40% Do not use SQV unless RTV boosted
Rifabutin RTV ↑ rifabutin 4-fold, ↓ rifabutin dose to 150mg/day, continue same dose of RTV
Rifabutin Other PIs ↑ rifabutin level and ↓ PI level ↓ rifabutin to 150mg/day and ↑ PI dose as appropriate
Phosphodiesterase-5 inhibitors (used for erectile dysfunction) All PIs ↑ blood levels and side-effects Use smallest possible dose
Methadone NNRTIs ↑ metabolism of methadone leading to withdrawal symptoms ↑ methadone dose
Simvastatin All PIs and DLV Large ↑ in simvastatin levels—↑ myositis Use pravastatin
* All PIs are substrate and inhibitors of cytochrome P450 (CYP450)—RTV the strongest, SQV the weakest.
* NNRTIs, NVP and EFZ induce CYP450.
* St John’s wort (Hypericum perforatum) is a strong inducer of CYP450 and should not be used with PIs or NNRTIs.

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Abnormal liver function test and hepatotoxicity Reported with all classes of antiretrovirals. ↑ in ♂ and in those with other predisposing risk factors e.g. excessive alcohol consumption, hepatitis B (HBV) and hepatitis C virus (HCV) infections. Abnormal LFTs graded from 1 (ALT 2–3 × upper limit of normal) to 4 (ALT >10 × upper limit of normal). Minor abnormalities do not require intervention apart from monitoring. Abnormal LFTs found in those on antiretroviral treatment:

  • NRTIs—commonly reported with DDI, D4T, and AZT. Hepatotoxicity— part of ABC hypersensitivity (usually associated with skin rash, fever, and eosinophilia)
  • NNRTIs—8% with EFZ and 15% NVP (hepatotoxicity in 4%). ♀ and those with higher CD4 count at ↑ risk.
  • PIs—up to 30%, most frequent with RTV containing regimens. Co-infection with HCV infection reported in most.

Avoidance and management Careful history including alcohol intake. Screen for HBV and HCV. Important to measure LFTs before starting HAART. Asymptomatic ↑ of ALT (especially grade 1–3) does not normally require any action apart from close monitoring, exclusion, and treatment of underlying aggravating factors. Isolated hyperbilirubinaemia 2° to IDV and ATZ not clinically significant. Specific action required with:

  • grade 4 ALT ↑—stop offending drugs;
  • symptomatic hepatotoxicity—stop all drugs until symptoms resolve. NVP should not be re-started if it was the cause;
  • symptomatic ↑ of ALT with hyperlacataemia—stop offending drugs;
  • ABC hypersensitivity reaction—stop immediately and do not rechallenge (fatal reaction).

Acute pancreatitis Most commonly implicated NRTIs are DDI (up to 7%) and D4T. They should not be combined. Possibly caused by mitochondrial toxicity or direct toxic effect of the pancreas. Risk ↑ in ♀ especially with CD4 <200cell/µL, excessive alcohol use and nutritional deficiencies. Presents with acute abdomen ± nausea and vomiting. Differentiate from other causes of acute abdomen e.g. cholecystitis and intestinal obstruction. Serum amylase usually ↑, may be normal (can also be ↑ in other causes of acute abdomen). DDI can ↑ salivary amylase, usually associated with sicca syndrome. Diagnostic accuracy higher if serum lipase also ↑. Ultrasound and CT scan of the abdomen may help establish diagnosis, extent of disease, and complications e.g. pancreatic abscess, pseudocyst. Management Monitor circulatory, renal, and liver functions (in a high dependency unit if necessary). Support with analgesia, fluid, and nutrition. Stop antiretrovirals or substitute the implicated drug with TDF or a non-NRTI regimen. P.523
Drug-related skin rash Skin reactions are common. Most frequently found with NNRTIs (NVP 16%, EFZ 4%) and ABC 8%. NVP induced rash typically occurs in first two weeks of therapy. An induction dose of half the maintenance dose for two weeks minimizes this risk. Typically maculopapular, affecting the trunk. Systemic symptoms occur with more severe reactions seen especially with ABC. Toxic epidermal necrolysis and Stevens–Johnson syndrome reported in 0.5%. Management Mild skin rash does not require intervention and will often settle spontaneously (with continuation of antiretrovirals). Antihistamines may be needed for symptomatic relief. More severe reactions need drug switching e.g. EFZ may replace NVP. ABC hypersensitivity reaction Occurs in ~4%, usually in the first 6 weeks of therapy (94%), median 11 days. Normally presents with ≥2 of following features: GI tract (nausea, vomiting, diarrhoea, pain), headache, fever, malaise, maculopapular or urticarial rash, abnormal LFTs, myalgia, dyspnoea, cough, respiratory distress, and eosinophilia. Once suspected, ABC should be stopped promptly and supportive treatment instituted. Symptoms, except rash resolve in 24–48 hours. ABC should not be used again as mortality from rechallenge is 4%. Lipodystrophy see p. 466. P.524
Immune reconstitution CD4 count ↑ on HAART mainly due to CD4 memory cells in first 4 months then followed by ↑ naïve cells associated with ↓ CD4 activation markers, due to ↓ viral replication. Initial phase of CD8 ↑ followed by a second phase of ↓. Most studies demonstrate ↓ HIV-specific immune responses and ↓ CD8 responses towards HIV. This contrasts with ↑ immune responses against other pathogens. ↓ incidence of OIs in patients who have higher CD4 counts from HAART. HIV damages thymus and lymphoid tissue at an early stage and may ↓ immune recovery. ↓ immune response may in part be due to failure of the thymus, as demonstrated by ↓ thymus emigrants measured in peripheral blood. The lower the CD4 nadir the slower and less complete immune reconstitution is likely to be. Immune recovery inflammatory response (IRIS) Inflammatory response induced by HAART occurring at sites of clinical and subclinical disease, usually seen in patients with CD4 count <100cells/µL at the initiation of therapy. The enhanced immunity is the likely mechanism converting a subclinical infection to an apparent symptomatic one due to the expansion of CD4 memory cells. Examples of IRIS include:

  • cytomegalovirus retinitis—4–8 weeks after HAART. Immune recovery uveitis may occur in patients with previous CMV retinitis. Patients with active and subclinical infection and those with CD4 <50/µL are at special risk.
  • HCV—restoration of HCV-specific responses occurs during HAART in patients with pre-existing HCV infection. Patients with negative HCV antibody but detectable HCV–RNA seroconvert with immune restoration. HCV–RNA levels ↑ with HAART especially if treatment is started when CD4 count >350cells/µL. Accompanied by transient ALT ↑.
  • Mycobacterium avium complex (MAC)—presents with localized disease e.g. painful lymphadenopathy or inflammatory masses associated with suppuration, unlike classical MAC where it is a disseminated infection. Due to the restoration of delayed hypersensitivity.
  • Herpes zoster—↑ by 5 times the expected rate, occurring in the first 4 months of HAART. Seen more frequently in those who develop a significant CD8 ↑.
  • TB—paradoxical tuberculous reaction e.g. ↑ in lymph node size, fever, and appearance of TB at other sites. Usually occurs in first 2 months (often 2–4 weeks) of starting TB therapy. Medication should not be routinely stopped. Steroids may be beneficial in controlling inflammatory process.
  • Herpes simplex virus—more frequent and severe disease occurs in patients responding to HAART.
  • Progressive multifocal leukoencephalopathy—may present for the first time or become worse in patients responding to HAART. Inflammatory brain changes (perivascular lymphocyte, macrophage, and plasma cell infiltrate) are more severe. CD8 seems to mediate the immunopathological process to JC virus.

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Frequently asked questions When do I start treatment? Treatment is usually started when the CD4 level ↓, ideally before itreaches 200cells/µL. The aim of treatment is to suppress viral replication, measured by the viral load (VL), and this should later be followed by ↑ in CD4 count. A combination of 3 antiretroviral drugs is usually used termed HAART (highly active antiretroviral therapy). What is drug resistance? The HIV virus can develop resistance by mutating so that it can replicatein spite of the antiretroviral treatment. This most commonly arises when medication is not taken reliably. If a person is infected with a drug resistant strain of HIV virus their treatment options will be ↓(some times severely). Do I need to use condoms even if my partner is also known to be HIV positive? Yes, it is important to practice safe sex to avoid superinfection (becoming infected with another strain of HIV) which may adversely affect the immune system and carry drug resistance. Does it matter if I forget to take my medication for a few days? Yes. It is very important that you take your anti-HIV drugs regularly. If doses are missed the virus may not be suppressed and there is ↑ risk of viral mutations and drug resistance. If my VL is undetectable, does it mean I am no longer infectious? No. An undetectable VL does not mean that there is no virus in the blood. It just means that there are too few particles to be detected on the test. There is still a risk of transmission with a low VL and so you must continue to practise safe sex. When will I get AIDS? Current therapy has had a dramatic effect in improving the well-being and life expectancy of people with HIV. Effective therapy makes HIV a chronic rather than a life-threatening infection. Therefore it is likely that you may not develop AIDS. Some people never need treatment but if it is started it must be taken consistently and probably for life. P.526
HIV drug resistance May be intrinsic, e.g. HIV-2 resistance to NNRTIs, or acquired as a result of mutations in viral proteins targeted by antiretroviral agents. Two factors drive mutations: high rate of viral replication (108–10virions produced daily) and error-prone reverse transcription (1 base pair substitution, deletion, insertion, recombination for every genome transcription). 1° mutation predates antiretroviral treatment which selects for it. 2° mutation develops during HAART and may be additive to 1°. HAART ↓ development of resistance by suppressing viral replication and thus generation of new variants. It can also suppress existing mutants if they are not resistant to all drugs in the regimen. However, resistance emerges if drug levels are insufficient to block viral replication but high enough to exert a positive selective pressure on these mutants. Even with undetectable VL low-level replication may allow resistance to develop. Drug resistance has been demonstrated in up to 25% of patients on HAART. Compensatory (2°) mutation reverses ↓ viral fitness resulting from other mutations. Some mutations induce resistance to certain agents while simultaneously producing hypersusceptibility to others (e.g. M184V ↑ sensitivity to AZT). Mutations Many mutations ↓ viral fitness. However, resistance mutations confer a selective advantage by ↓ susceptibility to antiviral agents, thereby enabling the mutant quasispecies to proliferate under treatment with those agents. Resistance mutations are described using a number referring to the affected codon (group of 3 nucleotides coding for an amino acid). A letter may be added after the number to denote amino acid in the mutant e.g. 74V (‘V’aline). This may be coupled with another preceding the number to show the wild type amino acid, e.g. L74V (‘L’eucine ← ‘V’aline). Resistance develops rapidly (within weeks of commencing treatment) if only a single mutation is required e.g. M184V (3TC, FTC) and K103N (NVP). It evolves more gradually if multiple mutations are required e.g. AZT, ABC, or PIs. Additional requirements may include a compensatory mutation e.g. 30N (NFV). K65R mutation (selected by TDF, ABC, DDI, and DDC) confers resistance to TDF, ABC, and 3TC and ↑ susceptibility to AZT and D4T. This mutation develops rapidly when regimens combining TDF with 2 of ABC, DDI or 3TC are given to the treatment naïve. Co-existence of K65R and M184V ↑ resistance to ABC and DDI but retains susceptibility to TDF, AZT, and D4T. Regimen with TDF must include AZT or a PI/NNRTI. Multiple mutations may interact. Prediction of resulting resistance patterns may be made by matching with resistance profile databases. This is provided by commercial resistance tests (e.g. Virtual Phenotype™). Databases of resistance profiles available at:

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Examples of resistance mutations (affected codons)

Nucleoside and nucleotide
3TC/FTC 184, 44, 118
ABC 65, 74, 115, 184
AZT/D4T 41, 44, 67, 70, 118, 210, 215, 219
  (Thymidine analogue mutations—TAMs, now known as multi-NRTI associated—NAMs)
DDI 65, 74
TDF 65, ≥3 NAMs including 41 or 210
Multi-nucleoside  
      â€˜151 complex’ 62, 75, 77, 116, 151
   69 insertion complex 41, 62, 67, 69 (insertion), 70, 210, 215, 219
NNRTI
Multi-NNRTI single 103, 106, 188
  requiring 2 100, 181, 190, 230
EFV or NVP   Any of above alone, 108, 188
Protease inhibitors
  major minor
APV 50V 10, 32, 46, 47, 54, 73, 90
ATV 50L 32, 46, 54, 71, 82, 84, 88, 90
IDV 46, 82, 84 10, 20, 24, 32, 36, 54, 71, 73, 77, 90
NFV 30, 90 10, 36, 46, 71, 77, 82, 84, 88
SQV 48, 90 10, 54, 71, 73, 77, 82, 84
RTV 82, 84 10, 20, 32, 33, 36, 46, 54, 71, 77, 90
LPV/RTV (4–6 required) 10, 20, 24, 32, 33, 46, 47, 50V, 53, 54, 63, 71, 73, 82, 84, 90  
Multiple (if >4) 10, 46, 54, 82, 84, 90 10, 54

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Persistence of mutation/resistance When treatment that selected for resistant quasispecies is discontinued wild-type virus usually becomes predominant within 2 months. Drug-resistant mutants occasionally remain dominant, e.g. 41L (zidovudine) but usually cease to be detectable by standard assay. However, they may still persist as minority quasispecies e.g. 90M (PI) or latent integrated proviral DNA (archived resistance). Standard assays therefore may not exclude drug resistance if carried out >1 month after stopping failing regimen. Interpretation of resistance mutations must take into account previous treatment history including evidence of viral persistence. Resistance testing Standard resistance assays require VL of ≥1000copies/mL and cannot detect minority species. Expert advice needed in interpreting results. Genotyping Viral genes sequenced to identify key mutations known to confer (alone or with others) resistance. Current methodology only detects viral mutants comprising at least 20–30% of the total population. Analysis is based on known correlation between genotype and phenotype from previous studies. Results normally available in ~4 weeks. Phenotyping Viral cell cultures are set up with increasing concentrations of antiretroviral drugs to determine IC50, the concentration of drug required to inhibit viral replication by 50%. Cut-off value indicates by which factor the IC50 of an HIV isolate can be ↑ while still being classified as susceptible (when compared with a wild-type control). IC50 above this value indicates resistance. Usually takes longer than genotyping. Efflux pumps P-glycoprotein (P-gp) and multi-drug resistance associated protein 1 (MRP1) are human cell membrane constituents, known as efflux pumps. Found in the lining of intestine, renal tubules, biliary canaliculi, capillaries in brain, testes, placenta; stem cells, lymphocytes, and macrophages. Their function is to protect tissues by actively transporting foreign substance out of cells. Cell membrane expression of P-gp/MRP1 and resulting activity of efflux pump vary depending on genetic polymorphism and induction or inhibition by various factors including HIV infection (↑ P-gp in advanced stage). PIs may be subject to efflux action resulting in ↓ absorption (intestinal P-gp) or ↓ levels in CD4 cells leading to ↓response to treatment with ↑ likelihood of resistance mutations. Clinical application of resistance testing Now recommended soon after diagnosis of HIV infection. It is particularly required in the following situations:

  • 1° infection (to identify transmitted resistance);
  • pregnancy (to ↑ likelihood of viral suppression in the short time scale);
  • virological failure of HAART (to guide choice of next regimen).

Studies suggest that HAART achieves better viral suppression when guided by resistance testing (with expert interpretation). P.529
P.530
When to switch and options Treatment switches may be required for intolerance, side-effects, metabolic disorders, or virological failure (defined as viral rebound or failure to achieve initial viral suppression). In patients where new 3-drug options (that are likely to fully suppress viral replication) are available, switches should be considered when there have been 2 or more consecutive viral loads >400copies/mL having excluded other explanations (e.g. intercurrent infection). Also important to exclude poor adherence or factors leading to ↓ drug levels before switching. Viral resistance testing should be done. Results may allow partial regimen change. If, due to previous treatment, decisions are difficult it may be wise to wait until VL has reached an amplifiable level before switching. Single drug switches can be made for drug related problems (e.g. side-effects) if satisfactory viral suppression. In the absence of resistance data first treatment switches are influenced by initial therapy. Options to consider for:

  • 2 NRTIs + PI regimens:
    • switch to 2 new NRTIs + a NNRTI;
    • if there is likely to be NRTI cross-resistance—a new boosted PI + a NNRTI and a new NRTI.

Amprenavir may retain activity after other PI failures and boosted lopinavir requires multiple resistance mutations to lose efficacy.

  • 2 NRTI + NNRTI regimens—switch to a boosted PI and 2 new NRTIs.
  • triple NRTI—switch to a PI + a NNRTI + a new NRTI.

Failing regimens may be continued if no viable treatment change possible. If viral load moderate and immune function stable residual antiviral activity is likely to be beneficial. Enfuvirtide—a complex 36 amino acid peptide that inhibits HIV (syncytium and non-syncytium inducing) fusion to CD4 cells. Its sequence is derived from HIV gp41. Has low potential for metabolic complications or drug interactions because of extracellular site of action. Resistance can develop by amino acid sequence changes in binding region of gp41 but unlikely to have cross resistance with other drug classes. Administered by sub-cutaneous injection (injection site reactions may occur). May be used as add-on therapy when no other options available for treatment change but in this situation resistance may develop quickly. The best use is in combination with conventional drugs optimized on the basis of resistance profiling. Other options include structured treatment interruptions to allow re-emergence of wild type virus and then to re-treat. However, there is likely to be a significant ↓ in CD4 count which may not recover on re-treatment (response may be limited due to the re-emergence of the resistant strains). Use of multiple drug combinations may have some medium term effect but suffer from major problems of tolerability. In addition to therapies aimed directly at the virus, treatments improving CD4 numbers or stimulating immune responses are options. P.531
Adjuvant therapy Immune therapy Pathogenesis of HIV is complex involving interactions between virus and immune system. Precise immune control of HIV infection not fully understood. HIV infection characterized by ↑ production of certain cytokines (e.g. interleukin (IL)1, IL6, tumour necrosis factor) and ↓ production of others (e.g. IL2, IL12, and interferon gamma). HAART partially reverses some immune abnormalities but most patients, even with full viral suppression, lack effective HIV-specific responses. Especially common if treatment commenced in advanced disease. Immune therapy may improve these responses. Cytokine therapy HIV infection results in gradual ↓ production and response to endogenous IL2. Synthesized by CD4 cells it induces proliferation and differentiation of CD4 and CD8 cells. IL2 given subcutaneously as an intermittent course produces ↑ CD4 count if given alone but more enhanced when combined with HAART. Viral load does not ↑ but long term effects unknown. Side-effects such as fever, tachycardia, hypotension, and respiratory failure are typically dose-dependent and can limit its use. Immune stimulation Endogenous (structured treatment interruptions) or exogenous antigens (therapeutic vaccination) are other ways of stimulating immune responses. Remune (Th1 stimulant) and ALVAC vcp 1452 are examples of therapeutic vaccines which have shown immunological benefit. Structured treatment interruptions Failure of HAART to restore HIV-specific immune responses may be related to loss of antigen presentation. Viral rebound following treatment interruption presents fresh HIV antigens to the immune system facilitating rapid response by resting memory cells. Structured treatment interruption allows for emergence of wild-type virus, more responsive to anti-retrovirals. It may be considered as a salvage therapeutic intervention for multi-drug resistance. Main drawbacks are a rapid rebound of virus, re-emergence of archived drug resistant virus, ↓ CD4 count and development of an acute retroviral syndrome. Hydroxyurea Acts by reducing cellular adenine (a nucleotide necessary for DNA synthesis) by inhibiting the enzymes needed for its production. It enhances antiretroviral activity (and toxicity) of adenosine analogues, such as DDI and induces cellular kinases that phosphorylate NRTIs, ↑ their antiretroviral activity (and toxicity). Main side-effects are bone marrow suppression (dose dependant), pancreatitis, and liver toxicity. Optimum dose unknown (usually given as 500mg twice daily) and so far no major trial evidence of benefit. P.532
Post-exposure prophylaxis (PEP) Following occupational or non-sexual contact Case-control study conducted by the US Centers for Disease Control (CDC) has shown that zidovudine PEP given to those occupationally exposed to HIV was associated with an 80% ↓ in infection. Combination treatment, demonstrably more potent and less likely to be affected by viral resistance, now recommended. Therefore consider if contact with HIV likely through:

  • percutaneous injury (e.g. from needles, instruments, bone fragments, bites which break the skin);
  • exposure of broken skin (e.g. abrasions, cuts, eczema);
  • exposure of mucous membranes (including the eye).

Average risk for HIV transmission after percutaneous exposure to HIV-infected blood in health care settings is ~3/1000 injuries. ↑ with large volumes of blood, deep injury, and high VL. After mucocutaneous exposure average risk is ~ 1/1000. No risk of HIV transmission if intact skin exposed to HIV-infected body fluids. If HIV status of source is unknown a designated doctor (not exposed worker) should obtain consent for HIV and other blood-borne virus testing. Management Wash skin or exposed wound with soap and water, without scrubbing and antiseptics. Bleeding of puncture wounds should be encouraged. Exposed mucous membranes, including conjunctivae, should be liberally irrigated with water, before and after removing any contact lenses. Following a discussion of risks and benefits, PEP should be recommended to HCPs if they have had a significant occupational exposure to blood or other high risk body fluid from someone either known to be HIV infected, or considered to be at high risk of HIV infection. PEP should be commenced as soon as possible after the event and should be continued for 4 weeks. UK DoH guidance states that PEP may still be worth considering even if 2 weeks have elapsed following exposure however studies suggest that delays >72 hours may render PEP ineffective. Following sexual contact Limited data but reports from Brazil and S. Africa suggest that PEP may provide some protection. Use of PEP following sexual exposure to HIV is only recommended within 72 hours of exposure (as early as possible). Risk benefit assessment should be made considering risk of transmission according to coital act (see box) and likelihood of source being HIV +ve (see p. 347). Other factors to consider include possibility of pre-existing HIV infection, and ability to adhere to/tolerate proposed antiretroviral regimen. P.533
Situations when PEP following sexual exposure is recommended (from BASHH guidelines)

  • Unprotected contact with known HIV +ve individual
    • receptive and insertive anal sex
    • receptive and insertive vaginal sex.
  • Unprotected contact with unknown HIV status where prevalence is >10%.
    • receptive anal sex.

PEP regimens

  • Combivir® (AZT 300mg + 3TC 150mg) twice daily + NFV 1.25g twice daily.
  • Alternatives for AZT are D4T or TDF and for NFV is LPV/RTV (Kaletra®).

PEP continued for 1 month. A negative antibody test 6 months after completing PEP confirms that infection has been avoided.

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