The most important issue to address in an adult with newly diagnosed HIV is adequate counseling and advice. The patient should then be staged and managed as clinically appropriate depending on stage of HIV disease and concurrent medical conditions. Potent combination antiretroviral therapy (ART) should be offered to all individuals with detectable HIV RNA regardless of CD4 cell count at the initial consultation. Immunization and prophylaxis for opportunistic infections should also be discussed and initiated as appropriate.
Guidelines suggest that, to optimize medication efficacy 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 program. Referral to a physician or infectious disease specialist 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, postexposure prophylaxis, HIV-related opportunistic infections, dermatological conditions, and mental status changes are beyond the scope of this topic and are dealt with in separate topics. See Overview of HIV.
Initial care and counseling
Counseling and lifestyle advice, consideration of nutritional needs, and supplementation are recommended in all patients. [ ]
A package of interventions including screening (i.e., for tuberculosis [TB] and cryptococcal antigen), treatment and/or prophylaxis for major opportunistic infections (i.e., trimethoprim/sulfamethoxazole prophylaxis, TB preventive treatment, and fluconazole prophylaxis), [ ] rapid ART initiation, and intensified adherence support interventions (i.e., tailored counseling to ensure optimal adherence to the package, including home visits if feasible) should be offered to all patients presenting with advanced disease.
Risk reduction counseling in HIV-positive people has been shown to be effective in reducing further transmission of HIV. This is particularly important during acute or primary HIV infection when plasma HIV levels are high and the patient is highly infectious. More than one session of counseling may be needed to result in a change in high-risk sexual behavior. Referral should be made to appropriate counselor/support groups for ongoing counseling sessions.
Counseling before initiating ART should focus on preparing the patient to commit to long-term ART.
Prevention and treatment of concomitant and opportunistic infections (OIs):
Concomitant and opportunistic infections are common in HIV-infected patients.
Primary prophylaxis against opportunistic infections including TB, Pneumocystis jirovecii, Mycobacterium avium complex, toxoplasmosis, and malaria (if required) is recommended.
Malnutrition is common in HIV disease, particularly in resource-poor areas. A cycle of opportunistic infection causing loss of weight and poor appetite, together with diarrhea and malabsorption, contributes to this malnutrition. Management would include ensuring an adequate balanced food source and early identification and management of OIs.
If the patient has concurrent hepatitis B infection, appropriate treatment should be used as part of ART. All patients with hepatitis C and HIV co-infection require treatment according to the latest guidance.
Prevention of comorbidities:
Routine primary prevention for chronic diseases of aging 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 abuse, and substance abuse should be included.
There is limited evidence of consistent clinically important benefits with micronutrient 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. [ ] [ ]
Vaccines should be given as early as possible in HIV infection or once the immune system has recovered on ART, as immune responses decrease with increased immunosuppression.
Recommended vaccinations include pneumococcal (pneumonia), meningococcal, influenza, hepatitis B, human papillomavirus, and tetanus/diphtheria/pertussis (a tetanus/diphtheria booster is required every 10 years). Additional vaccinations may be recommended depending on the patient’s age, risk factors for a specific disease, and previous vaccination history. Current local immunization schedules should be consulted.
Other vaccines may be recommended in travelers depending on the risk of acquiring a given disease in the area of travel (e.g., Japanese B encephalitis, inactivated typhoid, yellow fever, inactivated polio).
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/microliter. Other contraindicated vaccines include the Bacillus Calmette-Guérin (BCG), oral polio, typhoid, and yellow fever vaccines.
Starting antiretroviral therapy
ART is recommended for all HIV-infected patients, including those with acute or primary HIV infection, regardless of CD4 count; ART has been shown to reduce the risk of disease progression, decrease comorbid disease, and prevent HIV transmission. 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. World Health Organization (WHO) guidelines support the recommendation to initiate ART in all patients living with HIV, regardless of CD4 count.
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 virologic suppression. 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. One Cochrane review of seven randomized 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. 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 infection. [ ]
Choice of antiretrovirals
The choice of effective drug combinations requires expertise, particularly in complex cases. Providers must be competent in managing medication adherence and ART adverse effects, and anticipating drug interactions between HIV and non-HIV medications. 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: nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and pharmacokinetic enhancers or boosters (improve pharmacokinetic profiles of some antiretrovirals and increase their effectiveness, resulting in lower doses of the antiretroviral being needed). NRTIs, NNRTIs, and PIs are the antiretrovirals most commonly used and are the only classes available in regions such as southern Africa. INSTIs, while considered a first-line treatment in some countries, are generally only available in the developed world.
In most regions, a first-line ART regimen will generally consist of 2 NRTIs in combination with a third agent (usually an INSTI if available, or an NNRTI or boosted PI); 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. Local infectious disease specialists 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 virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, comorbid conditions, and cost.
Recommended initial regimens for most people with HIV (regimens have demonstrated durable virologic efficacy, good tolerability/toxicity profiles, and ease of use):
Bictegravir plus tenofovir alafenamide plus emtricitabine
Dolutegravir plus abacavir plus lamivudine (only for human leukocyte antigen [HLA]-B*5701 negative patients)
Dolutegravir plus tenofovir plus lamivudine or emtricitabine
Raltegravir plus tenofovir plus lamivudine or emtricitabine.
Guidelines now also recommend a two-drug regimen of dolutegravir plus lamivudine (an INSTI plus an NRTI) as an initial regimen for most people with HIV, except in patients with pretreatment HIV RNA >500,000 copies/mL or active hepatitis B co-infection, or those who will initiate ART before results of HIV genotype testing or hepatitis B virus testing are available. This recommendation is based on the results of two large, randomized controlled trials that showed that dolutegravir plus lamivudine was noninferior to dolutegravir plus tenofovir plus emtricitabine. A combination formulation of dolutegravir/lamivudine has been approved in the US and Europe as a complete regimen for the treatment of HIV-1 infection in adults with no ART history.
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):
Elvitegravir plus cobicistat plus tenofovir plus emtricitabine
Raltegravir plus abacavir plus lamivudine or emtricitabine (only for patients who are HLA-B*5701 negative and HIV RNA <100,000 copies/mL).
Ritonavir- or cobicistat-boosted darunavir plus tenofovir plus lamivudine or emtricitabine
Ritonavir- or cobicistat-boosted atazanavir plus tenofovir plus lamivudine or emtricitabine
Ritonavir- or cobicistat-boosted darunavir plus abacavir plus lamivudine or emtricitabine (only for patients who are HLA-B*5701 negative).
Doravirine plus tenofovir plus lamivudine or emtricitabine
Efavirenz plus tenofovir plus lamivudine or emtricitabine
Rilpivirine plus tenofovir plus lamivudine or emtricitabine (only for patients with HIV RNA <100,000 copies/mL and CD4 cell count >200 cells/microliter).
If ART is initiated before drug resistance testing and HLA B*5701 test results are available, one of the following regimens is recommended:
Bictegravir plus tenofovir alafenamide plus emtricitabine
Dolutegravir plus tenofovir plus lamivudine
Ritonavir- or cobicistat-boosted darunavir plus tenofovir plus lamivudine or emtricitabine.
Other two-drug regimens may be considered when abacavir or tenofovir cannot be used or are considered to be suboptimal:
Ritonavir-boosted darunavir plus raltegravir (only for patients with HIV RNA <100,000 copies/mL and CD4 count >200 cells/microliter)
Ritonavir-boosted darunavir plus lamivudine.
Other regimens for various clinical scenarios may be used; 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. 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 a first-line option when available. The WHO supports the use of a dolutegravir-based regimen first-line, with efavirenz-based regimens recommended as a suitable alternative.
Fixed-dose combination tablets that combine a number of drugs in 1 tablet are available, and can assist in improving medication compliance. Tenofovir is available as tenofovir disoproxil fumarate or the oral prodrug tenofovir alafenamide. Tenofovir alafenamide is available only in fixed-dose combination formulations with other antiretroviral agents. The prodrug is associated with less renal toxicity and less of an effect on bone mineral density, while tenofovir disoproxil fumarate is associated with lower lipid levels.
Dolutegravir should be used with caution in women of childbearing potential and those who are trying to conceive. Data has shown an increased risk of neural tube defects with dolutegravir-containing regimens (0.3%) compared with ART that does not contain dolutegravir (0.1%). It is not known whether this is a drug class effect. Therefore, before starting treatment with an INSTI, a pregnancy test should be performed. The benefits and risks of using dolutegravir around the time of conception should be discussed with women of childbearing potential. Dolutegravir is an alternative, rather than a preferred, option in individuals who are trying to conceive, as well as individuals who are not trying to conceive but who are sexually active and not using contraception. Dolutegravir may be used in individuals who are using effective contraception.
HIV RNA (viral load), CD4 counts, adherence, and adverse effects should be monitored to optimize and evaluate the efficacy of ART. For people with pretreatment drug resistance to NNRTIs, or people at high risk of pretreatment 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.
Once virologic suppression is achieved, regimen switching (within or between a class of drugs) may be considered in some patients, provided there is no evidence of viral resistance to the drugs in the new regimen. 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 jeopardizing 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. A three-drug regimen is usually recommended; however, there is emerging evidence that a two-drug regimen may also maintain virologic suppression. The Food and Drug Administration has approved dolutegravir/rilpivirine to treat adults with HIV-1 infection whose virus is currently suppressed on a stable regimen for at least 6 months, with no history of treatment failure and no known substitutions associated with resistance to the individual components. Monotherapy is not recommended. A specialist should be consulted before switching regimens.
Failure of first-line regimen
Virologic failure is defined as the inability to achieve or maintain suppression of viral replication to an HIV RNA level <200 copies/mL. Patients with virologic failure should be referred back to an HIV-experienced clinician or infectious disease specialist for further drug resistance testing, adherence assessment, and optimization of their treatment regimens based on drug resistance patterns.
Immunologic failure is failure to achieve and maintain an adequate CD4 response despite virologic suppression. These patients should also be referred to their specialist for assessment of current medications, untreated co-infections, and serious medical conditions.
If the initial regimen is not tolerated, a single drug switch within a drug class is an option, provided that the viral load is suppressed.
It is important to ensure and reassess medication compliance. This includes involvement of support structures such as a treatment partner and support groups. The patient should be counseled on the importance of adhering to the medication 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.
As the epidemic progresses, there is a greater recognition of the increases in non-AIDS comorbidities related to HIV disease. Such comorbidities include cardiovascular disease, renal disease, cancer, and bone and metabolic abnormalities.
People living with HIV are at increased risk of cardiovascular disease, both prior to and while taking ART. They are also at increased risk of renal disease, particularly older patients and those in the later stages of infection. ART reduces the risk of progression of renal disease. HIV-positive individuals are at an increased risk of osteoporosis and osteopenia compared with those who are HIV-negative. Vitamin D levels are often low in HIV-positive individuals. Some antiretrovirals (e.g., tenofovir disoproxil fumarate) may worsen renal and bone health.
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