HIV Infection

Introduction:
The human immunodeficiency virus (HIV) is a retrovirus, a virus built of RNA instead of more
typical DNA. It attacks the very cells of the immune system that should be protecting the body
against it – T lymphocytes and other white blood cells with CD4 receptors on their
surfaces.Acquired immunodeficiency syndrome (AIDS) is a chronic, potentially life-
threatening condition caused by the human immunodeficiency virus (HIV). By damaging
your immune system, HIV interferes with your body's ability to fight infection and
disease.According to the latest estimates from the Centers for Disease Control and Prevention,
approximately 36,400 new HIV infections occurred in the United States in
2018. Annual infections in the U.S. have been reduced by more than two-thirds since the
height of the epidemic in the mid-1980s.

Etiology:
 HIV infection is caused by the human immunodeficiency virus.
 HIV be caused  from contact with infected blood, semen, or vaginal fluids
 Common way of getting it is by sharing drug needles with someone who is infected
with HIV.

Pathophysiology:
HIV causes severe damage to the immune system and eventually destroys it by using the
DNA of CD4+ cells to replicate itself. In that process, the virus eventually destroys the
CD4+ cells. The immune system protects the body by recognizing antigens on invading
bacteria and viruses and reacting to them.
 CASE STUDIES
Case Study 1
Miss F is a 32-year-old legal secretary, originally from Zimbabwe, and has lived in
the UK for 10 years. She was diagnosed with HIV-1 2 years ago during a routine
sexual health screen. Her baseline CD4 count was 320 cells/mm3 and her viral
load was 37,000 copies/mL. She had no baseline resistance and was hepatitis B
immune and hepatitis C-negative. She was otherwise fit and well, taking only the
combined oral contraceptive pill and had no allergies. She had a male partner
who tested HIV-negative and they used condoms. She declines primary care
doctor disclosure around her HIV status, as she is worried about confidentiality. In
view of her CD4 count less than 350 cells/mm3 she was offered treatment. She
was keen on a single-tablet regimen and Eviplera (tenofovir disoproxil fumarate,
emtricitabine and rilpivirine) was started as a 1-pill once-a-day combination. This
was chosen because there are no significant interactions with the combined oral
contraceptive pill and it suited her lifestyle. In addition her viral load was less than
100,000 copies/mL, above which rilpivirine is not recommended in people starting
cART because of higher rates of virological failure. She tolerated this well and
achieved an undetectable viral load after 3 months, her CD4 count increased to
greater than 600 cell/mm3 and she remained stable. She is recalled to clinic due
to her viral load rising to 5697 copies/mL. A repeat sample confirms virological
failure (viral load 7812 copies/mL), and a resistance test confirms an E138K
mutation which confers resistance to rilpivirine.
Questions
1. What are the possible reasons for the rise in her viral load?
2. What ARV therapy change would you recommend?
3. What would you advise her to do regarding the combined oral contraceptive
pill?

Answers
1.There are three main reasons for virological failure. Firstly, the patient has
shown poor adherence to therapy, which should be explored in detail at this
patient’s appointment and support given around adherence if this has been the
main issue. Secondly, rilpivirine has a significant food requirement of 390 calories
to aid absorption and ensure adequate drug levels, so if she has been taking her
Eviplera without food, this could put her at risk of virological failure. Thirdly, a full
drug history needs to be taken. On discussion she reports that her primary care
doctor prescribed her omeprazole 20 mg daily for the last 3 months due to new
onset of dyspepsia. Omeprazole significantly decreases the rilpivirine plasma
concentrations caused by an increase in gastric pH; therefore, co-administration
in not recommended. This is the likely cause of virological failure in this patient. It
is important that patients are supported to disclose to their primary care
doctors/other clinicians and if they do not, that they seek advice from the
specialist HIV pharmacy team if they are prescribed a new drug or buy over-the-
counter medication.
2. She needs to switch her antiretroviral therapy because she is no longer
receiving an effective combination. If she remains taking Eviplera, she is at risk of
acquiring further drug resistance. The E138K mutation compromises rilpivirine
and also has cross-class resistance, so the other NNRTIs are no longer an option.
Tenofovir disoproxil fumarate and emtricitabine are still active; therefore, only
the third agent needs to be altered. The best option would be switching to a
boosted PI. As a class, the PIs are much more robust and require multiple
mutations to confer resistance; this strategy is recommended in the BHIVA (2015)
guidelines. Atazanavir should be avoided because it also interacts with proton
pump inhibitors. Therefore, ritonavir-boosted darunavir would be the third agent
of choice, particularly if there were any adherence concerns. Other third agent
choices would include an INI (raltegravir, elvitegravir or dolutegravir) or maraviroc
if the patient was CCR5 tropic. These agents would not be recommended if there
was any evidence of concurrent NRTI resistance.
3. Her contraception needs are important to consider because she is taking the
combined oral contraceptive pill. Rilpivirine did not interact; however,
darunavir/ritonavir will reduce its efficacy. Therefore, if she switches to this as a
third agent, then she would have to be counselled and offered alternative
contraception options. Medroxyprogesterone intramuscularly and the IUD/IUS
are viable options, but the combined oestrogen/progesterone and other
progesterone-based methods are less efficacious. If she switched to either
raltegravir, dolutegravir or maraviroc, she could continue with the combined oral
contraceptive pill because there are no significant drug–drug interactions.

Case Study 2
Mr C is a 58-year-old MSM who was recently diagnosed HIV through routine
sexual health testing at his local genitourinary clinic. He is a smoker of 12
cigarettes a day and has hypertension which is under control (blood
pressure120/95 mmHg) on ramipril and bendroflumethiazide and is also taking
pravastatin 40 mg once a day for high lipids. His fasting lipids were total
cholesterol 5.9 mmol/L, low-density lipoprotein cholesterol 4.5 mmol/L, high-
density lipoprotein 1.0 mmol/L, triglycerides 3.3 mmol/L. His height is 175 cm and
his weight is 82 kg. His CD4 count is 320 cells/mm3 and his viral load is 70,000
copies/mL. He has agreed to start ART, and baseline blood samples for renal
function and liver function tests, HIV drug resistance and HLAB5701 status have
been done. His calculated creatinine clearance (Cockcroft–Gault equation) was 73
mL/min. He has no drug resistance.

Questions
1. What assessments would you do to decide which NRTI backbone (Kivexa or
Truvada) Mr C should be prescribed?
2. What are the limitations of using the QRISK2 calculator? Is the calculated risk
likely to be an overestimate or underestimate?
3. Mr C is concerned about the implications of his cardiovascular risk review.
What information and advice should he be given?
4. Having considered all the issues, which backbone would you recommend?
5. What aspects need to be considered when determining the most suitable third
agent to prescribe for Mr C?

Answers
1. To determine the most appropriate medicine, Mr C’s HIV viral load should first
be reviewed. Because it is less than 100,000 copies/ mL, both backbones would
be appropriate. If it was more than 100,000 copies/mL, Kivexa would be excluded.
This would be followed by a cardiovascular risk assessment using the QRISK2-
2016 calculator (http://qrisk.org) to determine whether he would be suitable for
Kivexa (abacavir, one of the drugs in Kivexa, may be associated with an increased
risk of cardiovascular disease and would be best avoided if the cardiovascular risk
is >20%). His HLAB*5701 status would be reviewed and Kivexa would only be
considered if it was HLA-negative. Mr C would be assessed for any renal or
osteoporosis risks to establish whether Truvada would be suitable. His renal
function would be determined using the Cockcroft–Gault equation to ascertain
whether the combination Truvada was appropriate. His drug resistance results
would be reviewed to ascertain that whatever combination was prescribed would
result in viral suppression.
2. The main limitation of using the QRISK2 is that the population data
underpinning the calculator come from individuals whose HIV status was not
recorded. HIV infection itself is thought likely to increase the risk of cardiovascular
disease, and therefore the cardiovascular risk may need to be increased by a
factor of, for example, 1.6. Mr C’s calculated 10-year risk rate is 25.3%, and this is
likely to be an underestimate. Because abacavir may be associated with an
increased risk of cardiovascular disease and is best avoided if the cardiovascular
risk is greater than 20%, Kivexa may not be an appropriate choice.
3. Mr C should be given general lifestyle advice, especially to give up smoking,
follow a healthy, balanced diet and regular exercise. Specific lipid-lowering dietary
advice could be given. It would be useful to establish whether Mr C has changed
his lifestyle in the last 4–6 months, for example, change in adherence to lipid-
lowering therapy and/or change in diet. He should be encouraged to see his
primary care doctor for review of his lipid-lowering agent to optimise his lipids.
4. Given Mr C’s high cardiovascular risk, Kivexa would not be ideal, but Truvada
could be considered as a backbone.
5. Aspects to consider with respect to a third agent are Mr C’s concerns about pill
burden, how medicine taking would fit into his lifestyle, whether he would be
able to take raltegravir because this needs to be taken twice a day. If efavirenz is
being considered, then its potential to cause CNS side effects would need to be
reviewed with respect to Mr C’s work and whether this could compromise safety
in the workplace. In addition, if Mr C has had any mood problems they should be
explored because they can be exacerbated by efavirenz. Resistance to drugs like
efavirenz occurs if doses are missed. Therefore, if there was any likelihood that
Mr C is going to miss doses, which would result in drug resistance, it would be
better if Mr C was changed to a more robust regimen, for example, a PI-
containing regimen – darunavir/ritonavir or atazanavir/ritonavir. If Mr C was
taking any other concomitant medicines (e.g. stomach ulcer medicines like proton
pump inhibitors) then atazanavir/ritonavir would not be an appropriate choice
because of the drug–drug interactions. Therefore, the patient’s wishes, concerns,
lifestyle, as well as additional information (e.g. drug interactions), would be
considered when determining a suitable third agent in line with local policy for
the most cost-effective ARV therapy.

Case Study 3
Ms D is a 50-year-old social worker who was referred to the hospital accident and
emergency department by her primary care doctor following a 4-week history of
worsening respiratory symptoms, despite empirical treatment with amoxicillin,
followed by clarithromycin. She has lost 3 kg in the last 2 months, has had a non-
productive cough for 6 weeks and gets breathless climbing the stairs at home.
Pulse oximetry showed desaturation to 91% on exercise, and her arterial blood
gas sample had a PaO2 of 8.1 kPa. Chest radiograph showed bilateral interstitial
infiltrates. Her medical history includes irritable bowel syndrome (diagnosed 5
years ago), recurrent vaginal candidiasis for the past 7 years and allergic rhinitis,
for which she uses fluticasone nasal spray. She works in an inner-city area and has
no history of foreign travel outside mainland Europe. The hospital has recently
introduced routine (opt out) HIV testing for all acute medical admissions, as a
result of which Ms D was found to be HIV-positive, with a CD4 count of 47
cells/mm3.

Questions
1. What are the most likely HIV-related differential diagnoses for her respiratory
symptoms?
2. How should her respiratory symptoms be managed?
3. When should she start antiretroviral therapy?
4. What drug interactions would you need to consider when managing Ms D both
in the first few weeks and also in the longer-term?

Answers
1. The history, signs and symptoms (gradual onset, failure to respond to
treatment for community-acquired pneumonia, weight loss, non-productive
cough, breathlessness on exertion, oxygen desaturation, low PaO2 and chest
radiograph appearance) are all suggestive of PCP. However, some of these could
also be consistent with TB which she may have been exposed to as a result of the
nature of her job. TB would need to be excluded. Because Ms D has a significant
degree of immunosuppression, the possibility of more than one
pathogen/diagnosis must always be considered.
2. Until TB has been excluded, Ms D should be nursed in a negative pressure
room. A bronchoscopy should ideally be performed to assist diagnosis. She should
be started on treatment for PCP immediately with high-dose co-trimoxazole and
systemic corticosteroid (see text and Table 42.4 for doses and administration
details). Following induction treatment (usually 3 weeks in duration), she should
receive secondary prophylaxis until her CD4 count on fully suppressive
antiretroviral therapy is maintained above 200 cells/mm3 for 3–6 months. If she
responds well to PCP treatment and bronchial washings are negative for acid-fast
bacilli, then it would be reasonable for her to be managed expectantly with
regard to the possibility of TB, that is, not kept in isolation and not started on TB
treatment unless relevant symptoms persist or worsen, or new ones develop. If
TB treatment were required, the standard four-drug (rifampicin, isoniazid,
pyrazinamide, ethambutol) 2-month induction regimen, followed by 4 months of
rifampicin and isoniazid plus pyridoxine would be recommended.
3. With a CD4 count of 47 cells/mm3 , treatment with antiretroviral therapy
would be recommended as soon as possible. Depending on how well she
tolerated and responded to the PCP treatment, and whether TB treatment was
also needed, antiretroviral therapy would usually be started within 2–4 weeks of
diagnosis. For more information, refer to BHIVA guidelines for management of
opportunistic infections
4. If Ms D did require TB treatment, the hepatic enzyme induction effect of
rifampicin would need to be considered and a thorough review of drug–drug
interactions would be advised. The choice and dose of antiretroviral therapy
would also be affected if treatment was started after the HIV genotypic resistance
test result was known; if no resistance had been found, then efavirenz-containing
antiretroviral therapy would be possible. If co-administered with rifampicin, the
efavirenz dose should be increased to 800 mg once daily if her weight was greater
than 60 kg; if less than 60 kg, standard dosage of 600 mg should be used. If she is
experiencing side effects from efavirenz, TDM of efavirenz is recommended. If PI-
based antiretroviral therapy were initiated, either because of the presence of
resistance mutations or whilst awaiting the HIV resistance test result, then TB
therapy (if required) would need to be altered. Rifabutin (150 mg three times a
week e.g. Monday, Wednesday and Friday) would be used instead of rifampicin.
PIs also interact with intranasal and inhaled fluticasone and budesonide, resulting
in increased levels of these steroids, due to inhibition of cytochrome 4503A4 in
the gut wall and the liver and risk of increased steroid side effects and Cushing’s
syndrome. Beclometasone nasal spray would be a suitable alternative preparation
for Ms D’s allergic rhinitis and should be substituted.

Case Study 4
In 1997, Mr B, a 27-year-old man, presented with PCP. He had a CD4 count of 123
cells/mm3, and plasma HIV RNA was unknown because viral load testing was not
routinely available in clinics at the time. He had a good response to treatment
with high-dose cotrimoxazole and was subsequently commenced on triple-
combination therapy with stavudine, didanosine and indinavir. He continued
receiving this regimen for 2 years, until HIV RNA testing became available and he
was found to have a suppressed viral load and CD4 count of 412 cells/mm3. His
full antiretroviral therapy history, with reasons for switching, is detailed as follows
(Table 42.11). In April 2017 (now aged 47 years) his viral load remained <40
copies /ml, with CD4 count 670 cells/mm3. However, his creatinine clearance
(calculated using Cockcroft–Gault equation) was 41 mL/min and urine
protein/creatinine ratio (UPCR) was significantly raised, at 86 mg/mmol (normal
<30mg/mmol).Both were normal when last monitored 4 months previously. On
questioning, he revealed that he had been taking regular ibuprofen (400 mg three
times a day) for the past month, following a wrist fracture. His QRISK2 score was
calculated at 3.5%, and he is HLA-B*5701-negative Two weeks after stopping the
ibuprofen, Mr B’s creatinine clearance is now 52 mL/min and he is restarted on
Atripla 1 tablet daily. His repeat UPCR, 1 week after stopping ibuprofen was 42
mg/ mmol (improving), with normal urine albumin/creatinine ratio. His serum
phosphate was low and fractional excretion of phosphate was 35% (normal
<25%). Although his renal function was improving, it was decided to recommend
changing his antiretroviral therapy to Kivexa 1 tablet daily and efavirenz 600 mg
daily

Questions
1. What are the possible drug-related causes of Mr B’s renal dysfunction and
what alterations, if any, to his drug therapy would you recommend?
2. What information should Mr B be given about the proposed change of his
regimen to Kivexa plus efavirenz?

Answers
1. Tenofovir disoproxil fumarate use has been associated with renal dysfunction;
the first sign of which may be a raised UPreduced creatinine clearance, suggesting
moderate renal dysfunction, which may be tenofovir disoproxil fumarate related.
However, regular concomitant non-steroidal anti-inflammatory drugs may
increase the risk of renal dysfunction. It is possible that the addition of regular
ibuprofen has precipitated the renal dysfunction. Therefore, he would be advised
to change to an alternative analgesic, if one is still required, starting with regular
paracetamol. Tenofovir disoproxil fumarate has also been associated with
hypophosphataemia, a decrease in bone mineral density and other bone
abnormalities (infrequently contributing to fractures). With Mr B’s recent
fracture, this should be investigated via annual DEXA scanning. Atripla is not
recommended for patients with creatinine clearance less than 50 mL/min,
because the doses of emtricitabine and tenofovir disoproxil fumarate need to be
adjusted. For creatinine clearance 30–49 mL/min, a dosage of 200 mg
emtricitabine and 300 mg tenofovir disoproxil fumarate (245 mg tenofovir
disoproxil) every 48 hours is required. The efavirenz dosage remains 600 mg daily.
However, Mr B’s renal function must be closely monitored, for example, twice a
week, to ensure that the dosages are adjusted promptly to reflect any change.
This is to avoid over-dosing or under-dosing, and the associated risks of toxicity
and antiretroviral therapy failure. If the renal dysfunction continued or worsened,
despite stopping the ibuprofen and dose-adjusting his antiretroviral therapy, then
a change of antiretroviral therapy might be warranted.
2. Mr B is being switched from Atripla 1 tablet daily to Kivexa 1 tablet daily and
efavirenz 600 mg daily. The efavirenz component of his new regimen is also
contained in Atripla, and therefore is not new in terms of drug exposure, merely
as form of drug delivery. However, Kivexa is new for this patient. Points to include
when counselling Mr B on this new drug regimen are:
a. Why this change is being made: Mr B is demonstrating some toxicities of
tenofovir disoproxil fumarate, and it has been decided to stop treatment with this
drug to prevent any further renal deterioration. He also has a low phosphate level
with a recent bone fracture which may have been contributed to by tenofovir
disoproxil fumarate.
b. How to take this combination: It is best to take efavirenz at night to avoid any
disturbance in daily activities if Mr B has any CNS effects after taking his dose. He
is used to taking Atripla; therefore, both new drugs should be taken at the same
time as he has been used to taking his medication.
c. Adverse effects: Mr B is HLA-B*5701-negative and is therefore very unlikely to
develop a hypersensitivity reaction to abacavir (a component of Kivexa); however,
he should still be aware of this reaction. gastro-intestinal discomfort, respiratory
symptoms, lethargy, malaise, headache, elevated liver function tests and myalgia.
Symptoms usually appear within the first 6 weeks of initiation with abacavir,
although they can occur anytime. General side effects such as nausea, vomiting,
diarrhoea, fever, lethargy and rash are also present. Therefore, if Mr B has any of
these symptoms he should be carefully evaluated for the presence of a
hypersensitivity reaction. If Mr B experiences any worrying adverse effects, he
should present for review.
d. Monitoring and follow-up: Because Mr B is switching medication, he will need
to return within 2 weeks to be monitored for tolerance to the new medication.
This is in the form of a consultation, ideally with a pharmacist, to check whether
he is experiencing any side effects. He will also have a safety blood test (usually
liver function tests) at this stage to check for further potential adverse effects to
new medication and subsequently (usually at 4 weeks) more safety bloods tests
(usually liver and renal function tests) for viral suppression. At every review,
patients should be made aware of the ongoing plan for their care and ensure they
have enough medication to avoid any breaks in treatment.

Pain
Case Study
A 45-year-old woman, Mrs SG, presents to her primary care doctor with a 2-day
history of back pain after a lifting injury at work. The pain is constant and aching
in character with radiation into the posterior aspect of both thighs as far as the
knee. Physical examination shows Mrs SG to be maintaining a very rigid posture
with some spasm of the large muscles of the back. Her range of movement is very
poor, but there are no neurological signs in the legs.

Question
Which drugs may help Mrs SG’s pain? What other advice should Mrs SG be given?

Answer
 Acute back pain is very common and is rarely associated with serious spinal
pathology. The absence of neurological signs is reassuring and indicates that early
activity, possibly aided by a short course of analgesics, is the best way forward. A
short course of regular NSAID (e.g. ibuprofen 400 mg three times a day) is
recommended first-line treatment if not contraindicated. Paracetamol alone is
not now recommended. If unable to take a NSAID, paracetamol in combination
with a weak opioid is suggested. A muscle relaxant such as baclofen 20–40
mg/day in divided doses may be beneficial for short-term use only. The role of
opioids is less clear. Short-term use (7–14 days) of a weak opioid such as codeine
or tramadol is probably safe. Longer-term use is less satisfactory because there is
no clear evidence of efficacy, and sedative side effects may reduce the patient’s
capacity and motivation to remain active. Mrs SG should be advised to remain
active and accept that some pain is likely during the recovery phase. Failure to
remain active and, in particular, excessive bed rest are both associated with
worse outcomes.