- Patient presentation
- Differential Diagnosis
- Final Outcome
- Current ARV Treatment Guidelines in RSA
- Evaluation - Questions & answers
A 17 year old male presents to the hospital emergency room with a one week history of headache, fever, sore throat, painful swellings in the neck and muscle aches, requesting a malaria test.
Mr. L is a 17 year old male who lives in a community outside of Johannesburg. He shares a 3 roomed house with his parents and two younger brothers. They have electricity and running water. Both parents are employed and Mr. L is in his final year of high school.
One week ago:
He attended his local clinic with a headache and fever and was diagnosed with influenza. He was booked off school for 3 days and given amoxicillin 500mg pd. However, his symptoms have worsened over the past week.
Past medical and surgical history:
- His health throughout his childhood has been uneventful, with chickenpox at age 7 and two episodes of tonsillitis at age 5 and 12. He made a full recovery after each event.
- He has been fully vaccinated.
- He is not on any chronic medication and has no known allergies.
- He has had no previous surgery.
Family and Social history:
- Currently there is no one else ill at home.
- Mr. L has a smoking history of 1 pack per year.
- He consumes some alcohol (mostly beer) at the weekends, occasionally getting intoxicated (but cannot quantify).
- No recreational drug use.
- He does not have a girlfriend but has been sexually active with 5 different female partners in the last year. He occasionally uses condoms. His last sexual encounter was 3 weeks ago.
Mr L. travelled to Mozambique, one month ago (high risk season), with his parents. He took no malaria prophylaxis but took necessary precautions in the evening. He does not recall being bitten.
- Glandular Fever
- Acute retroviral syndrome
- BP: 105/55
- Temp: 39 degrees-C
- Respiratory rate: 24
- Pulse: 100
- Tender cervical and axillary lymph nodes
- No pallor
- No jaundice
- Erythematous pharynx, no exudate
- Fine maculopapular rash on face and trunk
- The rest of the examination was nil of note.
|WCC||3.0 x 10ˆ9/l||(4.00 – 10.00), atypical lymphocytes seen on diff|
|Hb||13.0 g/dl||(12.1 – 15.1 g/dl)|
|Platelets||100 x 10ˆ9/l||(150 – 400)|
|Urea Creatinine and Electrolytes|
|Na||138||(135 – 147 mmol/l)|
|K||4||(3.3 – 5.0 mmol/l)|
|Cl||100||(99 – 103 umol/l)|
|HC03||18||(18 – 29 mmol/l)|
|Urea||5.2||(2.5 – 6.4 mmol/l)|
|Creatinine||98||(62 – 115 mmol/l)|
|Paul Bunnell (for infectious mononucleosis)||Negative|
|Rapid HIV test||Negative|
|Throat Swab||No pathogenic bacteria isolated|
Three weeks later the patient returned for follow up. He was now asymptomatic with only cervical lymphadenopathy present on examination. A repeat rapid HIV test was conducted which was now positive.
On initial presentation of Mr L at the clinic, there was very little offered in terms of making a diagnosis. Clinically he presented with four signs of an inflammatory response- fever, pharyngitis, lymphadenopathy and rash. Upon followup three weeks later, his rapid HIV antibody test was positive. It was thus concluded that on the initial presentation at the clinic, he was acutely infected with HIV and was showing signs of acute retroviral syndrome.
Fever or elevation of body temperature is caused mainly by TNF-alpha, IL-1 and IL-6. These are termed endogenous pyrogens. These cytokines are a part of the innate immune system and cause the increase in the thermoregulatory set-point in the hypothalamus. Fever is generally beneficial because pathogens grow better at lower temperatures and adaptive immune responses are more intense at elevated temperatures. In this case, the initial inflammatory cytokine cascade allowed HIV to replicate.
Stages of HIV Infection
Let’s look at the different stages of HIV diagnosis in more detail, so that it is clear why Mr L was antibody negative at his first clinic visit. Graphic 1 shows Fiebig staging of laboratory testing for HIV infection.(Fiebig staging is a 6-stage classification system that was formulated for staging early HIV infection based on the different times viral markers and host antibody responses emerge. The system was named after the paper’s first author). It was likely that Mr L was first seen during the acute stage (Fiebig I/II), prior to seroconversion and when there was peak viraemia. It is known at this stage, there is a cytokine storm – where proinflammatory cytokine levels are high, giving rise to the fever, pharyngitis, lymphadenopathy and rash. As the peak viral load equilibriates to a set point, the ELISA test shows the presence of anti-p24 antibodies and the production of large amounts of viral proteins. These are detected in western blots.
The Immune Response to HIV
There appears to be an ordered series of events that occur upon HIV acquisition. Graphic 2 shows a typical immune response to untreated HIV infection. After transmission of HIV to a new host (1), there is dissemination of the virus to lymphoid tissues (2) and a rapid increase in viraemia in the acute phase (measured as Fiebig stage I). The fall in peak viraemia is thought to be due to the initial immune control (3) and viral loaddeclines to a setpoint. A decline in CD4+ T cells coincides with the increase in viral load. HIV-specific CD8+ Cytotoxic T cellresponses are thought to reduce systemic viral load and an increase in CD4+ T cells is often observed. HIV-specific binding antibodies appear after the reduction of viraemia, but antibodies are detectable by ELISA only later in acute infection (4, Fiebig stage III onwards). During chronic infection, CD4+ T cells decline slowly and viral load remains relatively stable. Neutralising antibodies begin to appear only after about 9 months and continued HIV replication and immune evasion exhausts the immune system leading to opportunistic infection and AIDS.
Let’s look at each of these four stages in closer detail:
1) HIV Transmission
Infection is a “rare” event. In 80% of cases, transmission infection is established by a single virus particle. All micro organisms that penetrate the epithelial surfaces are met immediately by cells and molecules that can mount an innate immune response.Epidermal Langerhans’ cells are a subset of dendritic cells found in the squamous epithelium of the female vagina and maleinner foreskin and are the first immune cells to contact HIV during heterosexual contact. They express surface CD207 (langerin)that captures virus by binding to gp120, which induces internalisation and degradation of virus particles. Activated Langerhans’ cells migrate to draining lymph nodes for antigen presentation to CD4+ and CD8+ T cells.In the process, CD4+ T cells can also become infected by virus bound to the Langerhans cell surface (trans-infection). Langerhans’ cells may also express CD4 and CCR5 and can become infected themselves. Activated Langerhans’ cells produce pro-inflammatory cytokines IL-1, IL-6 and TNF-alpha that, as discussed, can cause fever. Dilation and increased permeability of the blood vessels during inflammation leads to increased local blood flow and the leakage of fluid, and accounts for the heat, redness and swelling (pharyngitis)observed in Mr L’s acute retroviral syndrome.
2) HIV Dissemination
Afferent lymphatic vessels drain fluid from the tissues and carry antigen bearing cells from infected tissues to the lymph nodes where they are trapped. Follicles expand as B lymphocytes proliferate to form germinal centres and the entire lymph node enlarges. This would explain the clinical observation of lymphadenopathy. HIV infected CD4+ T cells, activated in genital draining lymph nodes, migrate to mucosal tissues such as the gut and skin. Dissemination of virus results in increased viral replication, mainly in lymph organs and leadsto high viral loads in peripheral blood. There is also a rapid depletion of CD4+ T helper cells, particularly in the gut lymphoid tissues. Tissue macrophages expressCD4 and CCR5 receptors and also become infected. Dendritic cells are CD4 negative but can capture HIV on surface CD209(DC-SIGN) molecules and mediate trans-infection of CCR5-bearing CD4+ T cells. Cutaneousimmune responses to HIV are thought to cause the maculopapular rash observed in Mr L, involving primarily the face and trunk. Localised anti-HIV skin responses have been shown experimentally in the macaque-SIV model. Although less common, hives and pruritic papules and pustules can occur on the extremities. A skin biopsy of the rash shows features similar to other viral exanthems and morbilliform drug eruptions. Most commonly, the dermis contains a superficial perivascular CD4+ lymphocytic infiltrate and the epidermis shows spongiosis with individual necrotic keratinocytes. The exact mechanism of how the rash forms remains poorly understood but is thought to be caused by homing of HIV-infected CD4+ T cells (expressing alphaEBeta7 integrin) to the skin that precipitates a local inflammatory response.
3) Control of Viraemia
The partial resolution of peak viral load observed during the acute stage of HIV infection is associated with robust T cell immunity. Tissue dendritic cells engulf virus detected in extracellular spaces and present viral peptides by both HLA class Iand II molecules in the lymph nodes to CD8+ and CD4+ T cells, respectively. Activated HIV-specific CD8+ cytotoxic Tlymphocytes impart viral control by killing HIV infected cells and reducing viral replication. This responseis not sufficient to eradicate the virus, but reduces viral load and allows CD4+ T helper lymphocyte numbers to increase. The absolute CD4+count does not however return to baseline levels but remains reduced.
As can be appreciated from the preceding discussion, there has been a multitude of immunological events occurring prior to seroconversion, many of them resulting in the clinical symptoms of acute retroviral syndrome. Antibodies to HIV (seroconversion) only begin to appear in peripheral blood 4-6weeks after transmission, but in rare instances can take up to 3 months. In order for HIV-specificantibodies to be generated there must be sufficient presentation of HIV antigens to B lymphocytes. This is achieved by captureof viral particles and proteins on the surface of follicular dendritic cells located in the lymphoid follicles (B cell zone) of the lymphnode. In addition, HIV-specific CD4+ helper T cells are required to provide activation signals for B cells to differentiate into plasma cells.
Based on the patient’s risky sexual practices he was offered voluntary counselling and testing (VCT). Blood was taken and a fourth generation HIV ELISA was used to detect both p24 antigen and HIV antibodies. This is the test of choice for detecting HIV infection during this stage. In fact, rapid tests are of limited value during primary HIV infection as specific antibody only becomes detectable in the blood towards the end of the symptomatic phase of the illness. However, due to the high initial viraemia, viral p24 antigen is invariably present during the symptomatic stage of primary HIV infection and can be used to diagnose infection at this stage.
During primary infection and the weeks following this period, the patient is highly infectious and must be advised to practice safe sex or abstain. Apart from reducing the patient’s infectivity, there is no clear benefit to early initiation of antiretroviral therapy in adults. Mr L should be referred to an ARV clinic for yearly monitoring of his CD4 count. Once his CD4 count falls below 350 cells per microliter or he develops an AIDS defining condition he should be started on ARV therapy.
Current ARV Treatment Guidelines in RSA
Current Guidelines in South Africa for Starting Antiretroviral (ARV) Treatment
ARV initiation is never an emergency, unless used for PEP or PMTCT. However, patients with profound immunosuppression are at significant risk of opportunistic illnesses, and should be assessed rapidly and initiated on ARVs as soon as adherence is assured. The following investigations are recommended prior to initiating ARVs:
- alanine transaminase (ALT)
- full blood count (FBC)
- serum creatinine and calculate creatinine clearance: avoid TDF if creatinine clearance is <50 ml/min; other NRTIs, except abacavir(ABC), require dose adjustment if creatinine clearance is <50 ml/min
- urinalysis for proteinuria
- hepatitis B surface antigen
- CD4 count
Where feasible, a serum or plasma cryptococcal antigen test should be performed in patients starting ARV with a CD4 count <100 cells/ul, to screen for early cryptococcal disease and to initiate pre-emptive treatment. In addition, a baseline HIV viral load should be performed where feasible. ARV treatment should be deferred until patients are prepared to commit to long-term treatment and maintaining good treatment adherence. However, efforts should be made to avoid lengthy indecision that may result in avoidable clinical deterioration and death.
Initial ARV Regimens for the Previously Untreated Patient
In accordance with international recommendations, the guidelines recommend the use of a reverse transcriptase inhibitor (NNRTI) and 2NRTIs (a safe dual NRTI combination) as the first-line ART regimen. In comparison with PIs, NNRTIs are better tolerated in the long-term and are at least as potent when combined with an appropriate dual NRTI combination. It is not recommend to use PI or an integrase inhibitor in first-line therapy, unless dictated by intolerance or NNRTI contra-indications. Either NVP or efavirenz (EFV) may be selected as the NNRTI, with EFV as the preferred NNRTI.
Although NVP is recommended it should be avoided in women with a CD4 count >250 cells/ul and men with a CD4 count >400cells/ul initiating ART for the first time, because of the increased risk of rash-associated hepatitis. It should be noted, however, that this side effect can occur at any CD4 count. Clinicians should also consider avoiding NVP in patients who may encounter difficulties getting rapid medical attention should rash or hepatitis symptoms occur. NVP should also be avoided in patients with pre-existent liver disease. When both NVP and EFV are contra-indicated, raltegravir (RAL) or a PI could be substituted. Any patient starting an NNRTI should be told to report a rash, jaundice or symptoms of hepatitis immediately.
Any of the following 2-drug NRTI combinations are recommended for use with the NNRTI:
- 3TC plus TDF, AZT or ABC
- emtricitabine (FTC) – a cytidine analogue very similar to 3TC –that is combined with TDF in a fixed-dose combination or with the addition of EFV as a triple-drug combination pill.
TDF is the favoured NRTI to use with 3TC (or FTC). Selection however will depend on affordability and co-morbidity (e.g. patients witha creatinine clearance <50 ml/min should not start TDF). If TDF is unavailable or contra-indicated, AZT should be used, provided that haemoglobin (Hb) is >10 g/dl.
D4T is a cheaper option than TDF, AZT and ABC, but it is considerably more toxic. Most public sector programmes in Southern Africa have discontinued D4T in first-line ART. Nonetheless, there is still a role for D4T in selected patients, when it is used in the short term in patients with contra-indications to other NRTIs. A common example is a patient with renal dysfunction and anaemia at baseline who could be started on D4T for 3 – 6 months and then switched to AZT or TDF depending on resolution of the anaemia and/or renal dysfunction. In addition, if there is a need for concomitant nephrotoxic medications,e.g. aminoglycosides to treat multidrug resistant (MDR)-TB, D4T (orAZT or ABC) is preferable to TDF during the period of exposure to the other nephrotoxic medication. Patients usually tolerate short-term D4Twell. Severe D4T side-effects, such as hyperlactataemia, lipo-atrophyand other mitochondrial toxicity, typically occur after 4 – 6 months,although peripheral neuropathy can develop earlier.
Therefore following the recommended guidelines, when Mr L is ready to be initiated on ARVs, his kidney function will be screened per recommendations and thereafter based on those results he will be started on a firstline regimen of EFV, 3TC plus TDF, AZT or ABC
Current Guidelines Regarding ARV Treatment and Malaria
Because one of the differential diagnoses was malaria, as Mr L had been to an endemic area, it is noteworthy to highlight several drug interactions between anti-malarials and ARVs:
1) Artemether-lumefantrine (Coartem) can be safely administered with NVP. There are no data yet on interactions with EFV, but the combination is likely to be safe. Boosted PIs dramatically increase the plasma concentrations of lumefantrine, but a dose reduction is not recommended, as the toxicity threshold of lumefantrine seems to be high. Close monitoring for toxicity is recommended when co-administering artemether-lumefantrine with ART.
2) Quinine concentrations are significantly decreased by LPV/r, probably due to induction of metabolism by ritonavir. It is likely that quinine concentrations will also be reduced by EFV and NVP;therefore, quinine should be avoided in patients receiving PIs orNNRTIs. Patients with severe malaria should receive artesunate and those with milder malaria should be treated with artemether lumefantrine.
3) Among drugs used for chemoprophylaxis, there are no clinically significant pharmacokinetic interactions between ARVs and mefloquine or doxycycline. However, mefloquine and EFV both cause frequent neuropsychiatric side-effects; therefore, doxycycline is the preferred chemoprophylactic agent for patients receiving EFV.
4) There are several interactions with atovaquone-proguanil (Malanil). Atovaquone concentrations are reduced by PIs and EFV. It is also likely that NVP decreases atovaquone concentrations. Proguanil concentrations are also reduced by PIs and EFV. Use of atovaquoneproguanil is therefore best avoided in patients receiving PIs or NNRTIs.
For additional recommendations including patients with TB, pregnant women and patients returning after defaulting on treatment – latest guidelines for ARVS in adults presented by the Southern African HIV Clinicians Society
Fiebig EW et al (2003) . Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS. 2003 Sep 5;17(13):1871-9.
McMichael AJ et al (2010). The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol. 2010 Jan;10(1):11-23.
Hladik F et al (2008). Setting the stage: host invasion by HIV. Nat Rev Immunol. 2008 Jun;8(6):447-57.
Cohen MS et al (2008). The spread, treatment, and prevention of HIV-1: evolution of a global pandemic. J Clin Invest. 2008 Apr;118(4):1244-54. doi: 10.1172/JCI34706.
Abrahams MR et al (2009). Quantitating the multiplicity of infection with human immunodeficiency virus type 1 subtype C reveals a non-poisson distribution of transmitted variants. J Virol. 2009 Apr;83(8):3556-67
Brenchley JM et al (2006). HIV disease: fallout from a mucosal catastrophe? Nat Immunol. 2006 Mar;7(3):235-9.
Sasseville VG et al (1998). Characterization of the cutaneous exanthem in macaques infected with a Nef gene variant of SIVmac239. J Invest Dermatol. 1998 Jun;110(6):894-901.
Evaluation – Questions & answers
What is the diagnosis
Approximately 50- 80% of patients who become infected with HIV experience an acute retroviral syndrome 2 to 4 weeks after becoming infected. Patients with this syndrome, all of whom are HIV antibody negative, typically present to primary healthcare providers or primary healthcare clinics. Recognition of acute HIV symptoms therefore requires provider awareness because these patients are at high risk of transmitting infection to sexual contacts.
When is risk of transmission highest
What is the window period
What should patients be advised to do during this time?
Why do rapid HIV tests give negative results even though a person has been infected?
Test your knowledge – Online Quiz