Approach
The most important issue to address in an adult with newly diagnosed HIV is adequate counselling and advice. The patient should then be staged and managed as clinically appropriate depending on stage of HIV and concurrent medical conditions. Antiretroviral therapy (ART) should be offered to all individuals with detectable HIV RNA regardless of CD4 count at the initial consultation. Immunisation and prophylaxis for opportunistic infections (OIs) should also be discussed and initiated as appropriate.
Guidelines suggest that, to optimise efficacy of treatment and quality of life, HIV primary care should be delivered by a clinician with HIV expertise, appropriate training, and experience, and who is also participating in an ongoing continuing education programme. Referral to a physician or infectious diseases consultant experienced in HIV management is preferable if the primary care physician does not have sufficient experience in managing patients on ART.
Treatment of pregnant women, post-exposure prophylaxis, HIV-related OIs, dermatological conditions, and mental status changes are beyond the scope of this topic and are dealt with in separate topics. The management of special patient populations (e.g., children, adolescents, older people, or transgender people; recipients of solid organ or haematopoietic cell transplants; patients with HIV-2; patients with hepatitis B or C, tuberculosis, or COVID-19 coinfection; patients with substance use disorders) and treatment-experienced patients is beyond the scope of this topic. See Overview of HIV for other available topics.
Supportive care and counselling
Counselling and lifestyle advice, consideration of nutritional needs, and supplementation are recommended in all patients.
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A package of interventions including screening (i.e., for tuberculosis [TB] and cryptococcal antigen), treatment and/or prophylaxis for major OIs (i.e., trimethoprim/sulfamethoxazole prophylaxis, TB preventive treatment, and cryptococcus pre-emptive therapy), rapid ART initiation, and intensified adherence support interventions (i.e., tailored counselling to ensure optimal adherence to the package, including home visits if feasible) should be offered to all patients presenting with advanced disease.[97]
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Counselling
Risk reduction counselling in HIV-positive people has been shown to be effective in reducing further transmission of HIV. This is particularly important during acute or primary infection when plasma HIV levels are high and the patient is highly infectious. More than one session of counselling may be needed to result in a change in high-risk sexual behaviour. Referral should be made to appropriate counsellor/support groups for on-going counselling sessions.[17][115]
Counselling before initiating ART should focus on preparing the patient to commit to long-term ART. Adherence to ART should be regularly assessed at every clinic visit.[78]
One Cochrane review found that simple ART adherence measures (e.g., self-reporting measures, tablet counts, electronic monitoring, pharmacy records) did not help identify patients who might not be taking their ART and who had higher viral loads. No one modality consistently offered a sufficiently high sensitivity to detect viral non‐suppression across groupings of similar measures.[116]
Prevention and treatment of concomitant infections and OIs
Concomitant infections and OIs are common in patients with HIV.
Primary prophylaxis against OIs including TB, Pneumocystis jirovecii, Mycobacterium avium complex, toxoplasmosis, and malaria (if required) is recommended.
Pre-emptive treatment for cryptococcal infection should be considered in certain patients.
Malnutrition is common in HIV, particularly in resource-poor areas. A cycle of OI causing loss of weight and poor appetite, together with diarrhoea and malabsorption, contributes to this malnutrition. Management would include ensuring an adequate balanced food source and early identification and management of OIs.[117][118]
If the patient has concurrent hepatitis B, appropriate treatment should be used as part of ART. All patients with hepatitis C and HIV coinfection require treatment according to the latest guidance.
Prevention of comorbidities
Routine primary prevention for chronic diseases of ageing is recommended based on age and risk. This includes risk assessment, screening, and testing for age-appropriate conditions such as cardiovascular disease, liver disease, diabetes, cancers, and bone disease. Assessment of diet, physical activity, smoking status, alcohol use, and substance use should be included.
Micronutrient supplementation
There is limited evidence of consistent clinically important benefits with micro-nutrient supplementation; however, most practitioners add a multivitamin and mineral combination supplement containing vitamins A, B6, B12, C, D, E and folate, with calcium, magnesium, iron, zinc, and selenium.[119][120] [
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There is some evidence that selenium supplementation can delay CD4 cell decline in patients with HIV; however, there is no quantifiable evidence that it reduces viral load.[121][122]Data on the benefits of omega-3 fatty acids supplementation are controversial, but some studies show that they may decrease serum inflammatory markers (e.g., C-reactive protein).[123]
Vaccination
Vaccines should be given as early as possible or once the immune system has recovered on ART, as immune responses decrease with increased immunosuppression.
Recommended vaccinations include:[124][91]
COVID-19
Hepatitis A
Hepatitis B
Human papillomavirus (HPV)
Influenza
Meningococcal
Pneumococcal
Tetanus, diphtheria, and pertussis
Herpes zoster
Additional vaccines may be recommended depending on the patient’s age, risk factors for a specific disease, and previous vaccination history (e.g., measles/mumps/rubella, mpox, respiratory syncytial virus). Other vaccines may be recommended in travellers depending on the risk of acquiring a given disease in the area of travel. Consult current local immunisation schedules for more information.
Live vaccines are generally contraindicated, particularly if immune compromise has already occurred. The measles-mumps-rubella (MMR) vaccine, varicella live vaccine, and herpes zoster live vaccine are contraindicated in patients with a CD4 count <200 cells/microlitre. Other contraindicated vaccines include the Bacillus Calmette-Guérin (BCG), oral polio, typhoid, and yellow fever vaccines.
Statin therapy
People living with HIV are at a greater risk of atherosclerotic cardiovascular disease (ASCVD).[127] Once ART has been started, virological suppression has been achieved, and opportunistic infections have been addressed, statin therapy may be considered.
The REPRIEVE study, a large randomised controlled trial undertaken in people living with HIV, demonstrated a significant reduction in major cardiovascular events in participants at low to moderate risk of cardiovascular disease who were receiving pitavastatin (a moderate-intensity statin) compared to those receiving placebo (35% reduction in major cardiovascular events after a median follow-up of 5.1 years).[125]
The US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents with HIV recommends statin therapy for primary prophylaxis in people with HIV who have low to intermediate (<20%) 10-year ASCVD risk estimates.[78]
Age 40-75 years with 10-year ASCVD risk estimate of 5% to <20%: initiate at least moderate-intensity statin therapy.
Age 40-75 years with 10-year ASCVD risk estimate of <5%: initiate at least moderate-intensity statin therapy, taking into account the presence or absence of HIV-related factors that can increase ASCVD risk (the absolute benefit is modest in these patients).
Age <40 years regardless of ASCVD risk: data are insufficient to recommend either for or against statin therapy in patients with HIV. Lifestyle recommendations are recommended in the general population, with statin therapy considered in select populations only.
Patients aged 40-75 years with 10-year ASCVD risk estimates ≥20% should be treated as per the general population based on evidence-based guidelines (i.e., high-intensity statin therapy).[78]
Guidelines may vary on their recommendations for statin therapy.
The Infectious Diseases Society of America (IDSA) recommends statin therapy for primary prevention in people with HIV aged 40-75 years, regardless of lipid levels and ASCVD risk. The recommendation is strongest for those with a 10-year ASCVD risk estimate of ≥5%. Evidence is insufficient to recommend either for or against statin therapy for people with HIV who are <40 years of age.[91]
The British HIV Association (BHIVA) recommends offering statin therapy to all HIV-positive people over the age of 40 years to reduce their risk of cardiovascular disease, regardless of their estimated ASCVD risk or lipid profile. Patients with an estimated 10-year ASCVD risk ≥5% should be prioritised for primary prophylaxis with a statin.[126]
Drug-drug interactions between statins and ART should be considered before starting treatment as dose adjustments may be required.
Starting ART
ART is recommended for all patients with HIV, including those with acute or primary infection, regardless of CD4 count; ART has been shown to reduce the risk of disease progression, decrease comorbid disease, and prevent HIV transmission.[78]
The strength of this recommendation was reinforced by the Strategic Timing of AntiRetroviral Treatment (START) study, which found that the risk of developing serious illness or death was reduced by 53% among those in the early treatment group, compared with those in the deferred treatment group.[128]
World Health Organization (WHO) guidelines support the recommendation to initiate ART in all patients living with HIV, regardless of CD4 count.[48]
ART should be started immediately (as soon as possible) after HIV diagnosis, including acute and recent infection, in order to increase the uptake of ART and linkage to care, decrease the time to viral suppression, reduce the risk of transmission, and improve the rate of virological suppression.[78]
The WHO recommends that rapid ART initiation (i.e., within 7 days of diagnosis, preferably on the same day as diagnosis in patients who are willing and ready to start treatment and there is no clinical contraindication) should be offered to all people living with HIV following a confirmed diagnosis and clinical assessment.[97]
One Cochrane review of seven randomised controlled trials (RCTs) with more than 18,000 adults found that rapid initiation (within 7 days of diagnosis) of ART probably results in greater viral suppression at 12 months compared with standard initiation in low- and middle-income settings.[129] [
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Rapid initiation of ART may be difficult to achieve in resource-limited settings.
Although ART has long-term adverse effects, these are minimal compared with complications of untreated HIV.
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Caution is recommended when starting ART in patients with OIs. Immediate initiation of ART may increase the risk of immune reconstitution inflammatory syndrome (IRIS) in patients with some OIs such as cryptococcal and TB meningitis.[78]
Choice of ART
The choice of effective drug combinations in treatment-naive patients requires expertise, particularly in complex cases. Providers must be competent in managing drug adherence and ART adverse effects, and anticipating drug interactions between HIV and non-HIV drugs. They must also be able to make drug and management modifications to maintain clinical benefits.
The classes of antiretrovirals that are currently in use include:
Integrase strand transfer inhibitors (INSTIs)
Nucleoside reverse transcriptase inhibitors (NRTIs)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Protease inhibitors (PIs)
Pharmacokinetic enhancers or boosters (improve pharmacokinetic profiles of some antiretrovirals and increase their effectiveness, resulting in lower doses of the antiretroviral being needed).
A first-line ART regimen will generally consist of two NRTIs in combination with a third agent (preferably an INSTI, or otherwise an NNRTI or boosted PI), or a two-drug regimen consisting of an INSTI plus an NRTI in select patients. However, guidelines and protocols may differ between countries and regions. Quadruple combination therapy has been found to be no more effective than triple combination therapy with currently available drugs.[130][131]
Local infectious disease consultants or HIV practitioners should be consulted and preferably patients referred to them for further management.
Given the number of effective options for initial therapy, selection of a regimen for a particular patient should be guided by factors such as virological efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, comorbid conditions, and cost.[78]
Specific ART regimens recommended in this section are based on guidelines published by the US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents with HIV.[78]
Recommended initial regimens for most people with HIV (regimens have demonstrated durable virological efficacy, good tolerability/toxicity profiles, and ease of use) without a history of prior use of long-acting cabotegravir as PrEP:[78]
INSTI-based regimens:
Bictegravir plus tenofovir alafenamide plus emtricitabine
Dolutegravir plus tenofovir disoproxil or tenofovir alafenamide plus lamivudine or emtricitabine.
Dolutegravir plus lamivudine (except for people with HIV RNA >500,000 copies/mL, hepatitis B coinfection, or in whom ART is to be started before the results of HIV genotype testing or hepatitis B virus testing are available).
Evidence supports the use of these first-line regimens.
Bictegravir plus tenofovir alafenamide plus emtricitabine has demonstrated high rates of virological suppression (97% based on a primary endpoint of viral load <50 copies/mL at 48 weeks) and low rates of discontinuation in treatment-naive patients, in one systematic review and meta-analysis of real-world data.[132]
The two-drug regimen of dolutegravir plus lamivudine has demonstrated comparable efficacy to bictegravir plus tenofovir alafenamide plus emtricitabine in treatment-naive patients up to 144 weeks of treatment with fewer adverse effects.[133]
People with HIV and a history of using long-acting cabotegravir as pre-exposure prophylaxis (PrEP) may require a different regimen.[78]
Long-acting cabotegravir has a long half-life and drug levels may persist in some people for up to 4 years at a suboptimal level, which may select for INSTI-resistant virus.
INSTI resistance may be present in those who become infected during (and possibly after) the use of long-acting cabotegravir. Therefore, INSTI genotypic resistance testing is recommended before starting ART, regardless of the amount of time since drug discontinuation.
INSTI-based regimens should not be started unless genotype tests show no INSTI-resistance mutations.
If treatment is started before results are obtained, the following non-INSTI regimen is recommended pending genotype results:
Ritonavir- or cobicistat-boosted darunavir plus tenofovir disoproxil or tenofovir alafenamide plus lamivudine or emtricitabine.
If an INSTI-based regimen is initiated and viral suppression is not achieved within 8-12 weeks, genotypic resistance testing (including for INSTIs) should be repeated.
Recommended initial regimens in certain clinical situations (these regimens are tolerable, but have some disadvantages compared with the first-line regimens above, or less supportive evidence) in people without a history of prior use of long-acting cabotegravir as PrEP:[78]
INSTI-based regimens:
Dolutegravir plus abacavir plus lamivudine (only for patients who are human leukocyte antigen [HLA]-B*5701 negative).
PI-based regimens:
Ritonavir- or cobicistat-boosted darunavir plus tenofovir disoproxil or tenofovir alafenamide plus lamivudine or emtricitabine
Ritonavir- or cobicistat-boosted darunavir plus abacavir plus lamivudine (only for patients who are HLA-B*5701 negative)
NNRTI-based regimens:
Doravirine plus tenofovir disoproxil plus lamivudine
Doravirine plus tenofovir alafenamide plus emtricitabine
Rilpivirine plus tenofovir alafenamide plus emtricitabine (only for patients with HIV RNA <100,000 copies/mL and CD4 count >200 cells/microlitre)
Other regimens for various clinical scenarios may be used (e.g., hepatitis B, hepatitis C, or tuberculosis co-infections); however, a specialist should be consulted when choosing other combinations.
The above regimens are recommended by the US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents with HIV.[78]
Other guidelines may recommend different regimens; however, most agree that second-generation INSTIs (bictegravir and dolutegravir) now offer the most advantages for the treatment of HIV and are generally preferred first-line options when available. The WHO supports the use of a dolutegravir-based regimen as first-line ART.[134]
Fixed-dose combination tablets that combine a number of drugs in one tablet are available, and can assist in improving compliance with ART regimens.
Tenofovir is available as tenofovir disoproxil or the oral prodrug tenofovir alafenamide. Tenofovir alafenamide is available only in fixed-dose combination formulations with other antiretroviral agents for this indication. The prodrug is associated with less renal toxicity and less of an effect on bone mineral density, while tenofovir disoproxil is associated with lower lipid levels.[78][135][136][137]
HIV RNA (viral load), CD4 counts, adherence, and adverse effects should be monitored to optimise and evaluate the efficacy of ART. See Monitoring.
For people with pre-treatment drug resistance to NNRTIs, or people at high risk of pre-treatment drug resistance to NNRTIs because of prior exposure to NNRTIs or from other risks, a non-NNRTI-containing regimen may be preferable. As individual level drug resistance testing isn’t available in most low- and middle-income countries, nationally representative data may be used.[138]
Once virological suppression is achieved, regimen switching (within or between a class of drugs) or optimising ART may be considered in some patients, provided there is no evidence of viral resistance to the drugs in the new regimen.[78]
A regimen may be switched, for example, to simplify regimens, enhance tolerability, decrease toxicity, prevent drug interactions, and reduce costs. The aim is to maintain viral suppression without jeopardising future treatment options.
The patient’s ART history should be reviewed, and any past instances of treatment failure and drug resistance should be taken into account when selecting a new regimen. Two- or three-drug regimens may be used.
A specialist should be consulted before switching regimens.
Failure of first-line regimen
Virological failure is defined as the inability to achieve or maintain suppression of viral replication to an HIV RNA level <200 copies/mL.[78] Patients with virological failure should be referred back to an HIV-experienced clinician or infectious diseases consultant for further drug resistance testing, adherence assessment, and optimisation of their treatment regimens based on drug resistance patterns.[78]
Immunological failure is failure to achieve and maintain an adequate CD4 response despite virological suppression.[139] These patients should also be referred to their consultant for assessment of current drugs, untreated coinfections, and serious medical conditions.
First-line INSTI-based regimens were associated with a lower risk of virological failure compared with PI-based regimens in one study. However, both INSTI- and PI-based regimens were associated with a higher risk of virological failure compared with NNRTI-based regimens, potentially due to channelling bias whereby non-adherent patients may have been more likely to be initiated on INSTI- or PI-based ART first line.[140] Resistance-associated mutations and virological failures were generally low with INSTIs in one systematic review, with the lowest number of virological failures in treatment-naive patients associated with bictegravir (0.6% to 1.4%) compared with dolutegravir (0.7% to 4%) and cabotegravir (0.6% to 9%).[141]
It is important to ensure and re-assess compliance with ART regimens. This includes involvement of support structures such as a treatment partner and support groups. The patient should be counselled on the importance of adhering to the dosing and timing at each visit. In cases of drug toxicity, the causative drug can be replaced by another, less toxic option without having to change the rest of the regimen.
Assessing and managing a patient who is experiencing ART failure can be complex. Drugs with a novel mechanism of action that the patient has not received before may be considered (e.g., cabotegravir and rilpivirine, ibalizumab, lenacapavir, fostemsavir, maraviroc).[78] Detailed information on the management of treatment-experienced patients is beyond the scope of this topic, and treatment-experienced patients should be managed by a specialist.
Non-AIDS-defining comorbidities
As the epidemic progresses, there is a greater recognition of the increases in non-AIDS comorbidities related to HIV. Such comorbidities include cardiovascular disease, renal disease, cancer, and bone and metabolic abnormalities.[142][143][144] See Complications.
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