Fame and Mortality: Evidence from a Retrospective Analysis of Singers
November 26, 2025
Free CME credits
Both our subscription plans include Free CME/CPD AMA PRA Category 1 credits.
Background
HIV was first recognized in 1981 in the United States when groups of young men showed up with unusual infections like Pneumocystis pneumonia and Kaposi sarcoma. These conditions are typically associated with severe immune deficiency. Researchers identified the virus in 1983 and since then more than 40 million people have died worldwide.
HIV is spread through sexual contact, shared needles and from mother to child. The patterns of transmission vary by region. Hepatitis B, hepatitis C and human herpesvirus 8 co-infections are common. HIV-1 is common and aggressive strain of the virus. HIV-2 is primarily found in West Africa, progresses more slowly and is more difficult to spread.
HIV’s origins come from cross-species transfer from primates in Africa after which the virus spread quickly along trade routes. Stigma, misinformation and political denial worsened the epidemic. These factors discouraged testing and delayed treatment even when effective therapies became available.
HIV is manageable and allows to livelong because of advancements in antiretroviral therapy (ART), prevention and diagnosis. About 39 million people had HIV by 2022, with two-thirds of those individuals living in Africa. This indicates continued transmission as well as increased survival. ART can save lives but it has potential side effects, requires lifelong commitment and does not cure HIV. High costs are incurred by patients and healthcare systems as a result of the epidemic, and obstacles such as stigma, restricted access to care, and financial constraints still prevent universal treatment.
The WHO and UNAIDS are two international health organizations have set aggressive 95-95-95 goals. By 2025, 95% of people with HIV should be aware of their status, 95% of those who have been diagnosed should be taking antiretroviral therapy, and 95% of patients who have received treatment should have viral suppression. Reaching these goals relies not only on medical progress but also on supportive social and policy environments, integration of HIV services with other healthcare needs and community-driven efforts to increase access and fight discrimination.
Epidemiology
HIV is a major global health concern. HIV-1 causes the majority of infections and HIV-2 contributes a small fraction. In 2022, 39 million people were living with HIV globally mainly in Sub-Saharan Africa. Global trends show progress specifically in eastern and southern Africa where new infections and AIDS-related deaths have decreased to 50% till 2010. HIV incidence has increased significantly in the Middle East, North Africa, Eastern Europe and Central Asia areas because of stigma, weak health systems and conflict.
Gender disparities in the HIV epidemiology are pronounced with women have the majority of new infections globally. Addressing these disparities is essential to reducing new transmissions. The UNAIDS and WHO identify five populations at highest risk which include men who have sex with men, sex workers, incarcerated individuals, people who inject drugs and transgender or gender-diverse persons. Most transmissions occur through sexual contact, with heterosexual spread dominating in Africa and same-sex transmission more common in many other regions.
Anatomy
Pathophysiology
HIV is part of the Retroviridae family. This family is unique because its RNA genome changes into DNA before it integrates into the host’s genome. This process leads to lifelong infection. HIV-1 is the well-known and prevalent of two primary species. HIV-2 spreads more slowly and is primarily found in West Africa. Since these cells express the CD4 receptor, the primary site for viral entry, CD4+ T lymphocytes and macrophages are the primary targets of both viruses. By attaching to CD4 and the chemokine co-receptors CCR5 or CXCR4, the viral envelope glycoproteins facilitate this..
Once inside, the HIV-1 capsid usually stays intact until it reaches the nuclear pore complex. Recent studies show that reverse transcription happens in or just after nuclear import. This challenges older ideas that this process took place in the cytoplasm. The viral reverse transcriptase enzyme starts DNA synthesis using host transfer RNA as a primer. HIV is a viral infection caused by a negative-sense DNA strand that is used to create complementary DNA, forming a double-stranded viral genome. The viral integrase inserts this DNA into the host’s chromatin, establishing a proviral state. The viral genome serves as a template for new virions and lead to infection. HIV is found in lymph nodes in two days of mucosal exposure and systemic plasma viremia usually appears within three days. Genetic variability is a key feature of HIV pathogenesis and a significant challenge in treatment. The viral reverse transcriptase has an error rate 100 to 1,000 times higher than cellular DNA polymerases, leading to frequent point mutations.
HIV also disrupts humoral immunity, especially within B-cell follicles. Follicular helper and regulatory T cells, along with the limited presence of follicular CD8+ cytotoxic T cells, lead to weak antibody responses and the survival of viral reservoirs. These immune sanctuaries persist in patients receiving ART, making viral eradication particularly difficult.
Etiology
HIV is part of the Retroviridae family and the Lentivirus genus. It mainly infects CD4+ T-helper lymphocytes, which leads to gradual immune suppression. This can weaken the body’s defense system and make people more susceptible to opportunistic infection. If untreated, the infection progresses to AIDS. This stage is characterized by severe immunodeficiency and serious health issues.
HIV-1 and HIV-2 are the two primary types of the virus. Each variety originates from distinct simian immunodeficiency virus transmissions across species. HIV-1 and HIV-2 are different in terms of their severity, ease of transmission and health consequences. Only roughly 48% of the nucleotide sequences and 60% of the amino acid sequences of HIV-1 and HIV-2 are similar on a molecular level.
A conical protein capsid is encased in a lipid envelope in both virus types. Important viral enzymes like reverse transcriptase, integrase and nucleocapsid proteins are present in this capsid along with two identical RNA genomes. Contact with infected bodily fluids like blood, semen, vaginal and rectal secretions, breast milk and amniotic fluid can spread virus. Unprotected sex, mother-to-child transmission during pregnancy or delivery and sharing contaminated syringes or medical equipment are common ways of transmission.
Genetics
Prognostic Factors
HIV infection is fatal without treatment. The effective antiretroviral therapy (ART) has transformed prognosis. Sustained virologic suppression with ART significantly improves survival, with life expectancy varying by age of initiation and regional resources. A 2017 meta-analysis estimated that starting ART at age 20 confers an average life expectancy of 43.3 years in high-income countries and 28.3 years in low- and middle-income regions. Delayed initiation at age 35 reduces this to 32.2 and 25.6 years, respectively. These gains reflect advances in therapy, earlier treatment initiation, and improved adherence and socioeconomic support.
The most critical determinant of outcome is durable viral suppression. Patients who maintain viral suppression but fail to achieve immunologic recovery (CD4+ <200 cells/mmÂł) experience a 2.6-fold higher risk of all-cause mortality compared with those whose CD4+ counts recover. Initiating ART at the time of diagnosis improves immune reconstitution and clinical outcomes, whereas delaying therapy until CD4+ levels fall below 200 cells/mmÂł markedly reduces the chance of full immune recovery and increases AIDS and non-AIDS morbidity.
Clinical History
History
When evaluating patients with confirmed or suspected HIV, a thorough medical history is crucial. In order to find symptoms that could indicate opportunistic infections or HIV-related complications, this process combines a review of systems with focused questioning. Finding coexisting conditions and staging the infection are further benefits of a thorough history.
Risk factor assessment is critical and should be approached in a nonjudgmental manner. Sexual history including the number of partners, sexual behaviors, use of barrier protection and history of STIs and knowledge of partner’s HIV status are important components. The kind of drug, how often it is used, how it is administered, and whether injection supplies are shared should all be included in a substance use history. Additionally, a history of blood transfusions should be documented.
Because depression, mental illness and substance use disorders can make it difficult to stick with therapy, mental health screening is essential. To find gaps in vaccine-preventable disease coverage, vaccination history should be examined. This is especially important for pneumococcal and hepatitis B infections, which are serious risks for individuals with HIV. Living conditions, support networks, money, insurance, stigma, coping mechanisms and possible exposure to violence are all examined in social history since they have an impact on adherence and care access.
Staging frameworks provide context for disease progression. The U.S. NIH describes acute HIV, chronic HIV, and AIDS as sequential stages, while the CDC uses a classification system based on CD4+ counts and AIDS-defining illnesses. The WHO additionally employs a staging method relying on clinical presentation in areas with limited CD4+ testing.
Physical Examination
The physical examination in patients who have HIV focuses on identify the findings that correlate with the stage of infection and possible opportunistic diseases.
AIDS: In advanced disease, physical findings reflect opportunistic infection and malignancies, including pulmonary or gastrointestinal candidiasis, invasive cervical cancer, cryptococcal meningitis, cytomegalovirus retinitis, Kaposi sarcoma, tuberculosis, HIV encephalopathy, non-Hodgkin and Burkitt lymphomas, Pneumocystis jirovecii pneumonia, progressive multifocal leukoencephalopathy, Salmonella septicemia, and HIV-associated wasting. These are linked to profound immunosuppression typically with CD4+ counts below 200 cells/mmÂł.
Age group
Associated comorbidity
Associated activity
Acuity of presentation
Differential Diagnoses
HIV must be considered in patient who have recurrent severe infection. Other diseases which can have same effects on immune system of patients are:
Severe combined immune deficiency syndrome
Severe malnutrition
Chemotherapy induced immunosuppression
The differential diagnosis in patient who have acute HIV are:
Systemic lupus erythematosus (SLE)
Viral hepatitis
Toxoplasmosis
Mononucleosis
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
HIV treatment aims to prevent the immune system deterioration and reduce the risk of opportunistic infections, AIDS-defining illnesses and non-AIDS-related complications. It improves the survival and quality of life by restoring the immune function, suppressing viral replication and decreasing HIV-related morbidity. Highly active antiretroviral therapy (HAART) along with combined antiretroviral therapy (ART) is the cornerstone of management. Effective treatment reduces the risk of immune reconstitution inflammatory syndrome (IRIS), improves CD4 T-cell recovery and partially restores immune repertoire. Long-term use of HAART reduces psychiatric and renal comorbidities, but risks may persist.
Antiretroviral Therapy (ART)
Classes of antiretroviral drugs include:
ART is prescribed in combination regimens, usually consisting of two NRTIs plus an agent from another class, most often an INSTI. Treatment must be individualized on the basis of viral load, CD4 count, comorbid conditions, drug resistance profile, potential side effects, pill burden and drug–drug interactions.
Two major guideline sources the U.S. Department of Health and Human Services (DHHS) and the International AIDS Society–USA Panel (IAS-USA) provide updated treatment standards. Both recommend early and universal initiation of ART for all patients with HIV, regardless of CD4 count, with “rapid start” favored where possible.
Historically, ART was delayed until CD4 counts fell below 200 cells/µL. However, multiple cohort studies and clinical trials including the NIH CIPRA HT 001 study demonstrated improved survival, reduced tuberculosis incidence, and lower overall mortality when ART was initiated earlier (CD4 200–350 cells/µL). Modern practice now supports immediate ART initiation at diagnosis, unless contraindicated by acute opportunistic infections.
Rapid ART start: Trials in Lesotho, Haiti, and South Africa demonstrated improved virologic suppression and patient retention with same-day initiation. U.S. programs in San Francisco and New York City have successfully implemented rapid-start protocols, achieving shorter times to viral suppression and improved linkage to care. Rapid start is recommended in all patients who are clinically ready and without contraindications.
Recent trials show that INSTI-based regimens are superior to older NNRTI-based regimens with higher suppression rates and fewer adverse effects. Dolutegravir and bictegravir are now first-line because of their potency, tolerability and resistance barriers. Studies have showed that  raltegravir and dolutegravir have better virologic suppression and fewer side effects compared to efavirenz. Fixed-dose combinations and newer formulations improve adherence through single-tablet regimens. Short-course ART combined with single-dose nevirapine reduces vertical transmission and minimizes resistance development in pregnancy.
Use of Prophylaxis for Opportunistic Infections
The prevention of opportunistic infection is a necessary in HIV care specifically in patients who have severe immunosuppression. Pneumocystis jirovecii pneumonia (PCP) is the common and avoidable consequence. Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is recommended when CD4 count falls below 200/µL. If immune recovery occurs and CD4 counts remain above 200/µL with effective ART, PCP prophylaxis can be safely discontinued. In patients unable to tolerate TMP-SMX, alternatives include dapsone (following G6PD deficiency screening), atovaquone, or monthly inhaled pentamidine.
Because TMP-SMX also protects against toxoplasmosis, it should be initiated in patients with CD4 counts below 100/µL if not already prescribed for PCP prevention.
When CD4 counts decline to <50/µL, the risk of Mycobacterium avium complex (MAC) infection increases. Weekly azithromycin or clarithromycin is effective prophylaxis, though recent evidence suggests that routine primary prophylaxis is unnecessary in patients on suppressive ART due to markedly reduced incidence and mortality.
Routine prophylaxis against fungal or viral infections is not generally recommended. However, fluconazole may be considered for patients with very low CD4 counts (<50/µL) in areas with high rates of histoplasmosis or coccidioidomycosis, although its use raises concerns about drug resistance, especially in Candida species.
For cytomegalovirus (CMV), oral ganciclovir has been shown to lower the risk of invasive disease by about 50% in advanced AIDS. Nonetheless, due to potential resistance, it should be reserved for patients with CD4 counts below 50/µL who also have evidence of prior CMV infection.
Treatment of HIV-Associated Lipodystrophy
HIV-associated lipodystrophy is characterized by either central fat gain or regional fat loss in individuals on antiretroviral treatment. To address this issue, the FDA authorized tesamorelin (Egrifta) in 2010 to reduce extra visceral belly fat in patients.
The results of two major, multicenter, phase III, randomized, double-blind, placebo-controlled studies supported the approval. These investigations, which included approximately 800 HIV-infected individuals with abdominal fat buildup, included two phases: a 26-week therapy phase and a 26-week extension phase. Tesamorelin dramatically decreased visceral adipose tissue by week 26, and the benefits persisted until week 52. Decreases in abdominal fat were associated with improvements in metabolic parameters such as cholesterol and glucose management, emphasizing the therapeutic effects for both body composition and metabolism.
Suppressive Therapy for Herpes Simplex Virus 2 Infection
Co-infection with herpes simplex virus type 2 (HSV-2) is widespread among HIV-1 patients. Acyclovir-based suppressive treatment has been proven in studies to reduce plasma HIV-1 levels and moderately impede progression.
In a large, randomized study involving 3,381 HIV-1/HSV-2 coinfected patients who were not yet on antiretroviral therapy and had CD4 counts ≥250/μL, acyclovir (400 mg orally twice daily) reduced the overall risk of HIV-1 progression by 16% compared with placebo. Progression was defined as the first decline in CD4 T-cell counts below 200/μL.
Notably, among participants with baseline CD4 counts ≥350/μL, acyclovir use delayed the decline to below 350/μL by 19%, suggesting potential benefit in early disease stages. These findings highlight acyclovir’s role in modifying HIV-1 dynamics through HSV-2 suppression. However, further investigation is needed to clarify whether acyclovir prophylaxis prior to starting ART provides long-term benefit in slowing HIV progression.
Management of HIV-Associated Diarrhea
Diarrhea is a common consequence of HIV/AIDS, especially in people undergoing antiretroviral medication (ART). To address this, the US Food and Drug Administration (FDA) authorized rofelemer in December 2012 as a treatment alternative for symptom reduction in these individuals.
Before initiating rofelemer, it is essential to rule out secondary causes, including infectious pathogens or underlying gastrointestinal diseases, since targeted management of these conditions may be required. Once other etiologies are excluded, rofelemer provides a safe and effective means to reduce diarrhea, thereby improving quality of life and adherence to ART regimens.
Medication
Use of Antiretroviral Therapy (ART) in HIV Infection
Importance of ART
Effective antiretroviral therapy (ART) remains the cornerstone of HIV management, as it significantly improves survival, enhances quality of life, and prevents opportunistic infections. Standard therapy involves combinations of antiretroviral drugs, selected according to established guidelines, and tailored to patient-specific factors such as prior treatment exposure, comorbidities (e.g., hepatitis C coinfection), and drug resistance patterns.
Antiretroviral Drug Classes
ART agents fall into multiple pharmacologic categories, each targeting distinct steps in the viral replication cycle:
Combination Therapy and Resistance
Combination ART, often termed highly active ART (HAART), is the standard of care because:
Ritonavir is now primarily used as a pharmacokinetic booster. It enhances the bioavailability of coadministered protease inhibitors.
Fixed-Dose Combination Products
To improve adherence and simplify regimens, numerous once-daily fixed-dose combinations are available, such as:
These regimens reduce pill burden, improve compliance, and maintain viral suppression with fewer side effects.
Clinical Trial Evidence for Regimen Effectiveness
Pediatric Considerations
Several ART drugs initially approved for adults/adolescents are now FDA-approved for children, with dosing adjustments. New formulations like tenofovir alafenamide (TAF) are preferred because of improved renal and bone safety compared with tenofovir DF.
Use of Antiretroviral agent, nucleoside reverse-transcriptase inhibitor
NRTIs agents inhibit the viral replication by suppressing viral RNA dependent DNA polymerase.
Abacavir (Ziagen): It is an NRTI which inhibits HIV viral replication by blocking the RNA-dependent DNA polymerase. Patients should be screened for HLA-B*5701 before starting the treatment to reduce the risk of hypersensitivity reactions.
Didanosine: It interferes with the HIV viral RNA dependent DNA polymerase and inhibits the viral replication.
Emtricitabine: It is a synthetic nucleoside cytosine analog. It works by competing with deoxycytidine-5′-triphosphate, incorporating into viral DNA, and causing chain termination to inhibit HIV replication.
Lamivudine: It is a thymidine agent which inhibits the viral replication.
Tenofovir disoproxil fumarate (TDF): It is a prodrug that inhibits HIV reverse transcriptase. It is competing with deoxyadenosine 5′-triphosphate and causing DNA chain termination. It is converted to tenofovir in the body, has enhanced bioavailability with high-fat meals, allows once-daily dosing, and has demonstrated efficacy in PrEP trials for IV drug users and heterosexually active adults, though its use is not recommended for MSM.
Zidovudine (Retrovir): It is a thymidine analog which inhibits the HIV replication by interfering with viral DNA synthesis.
Use of Antiretroviral Agent, Protease Inhibitor
Protease Inhibitors (PIs) block HIV protease, preventing cleavage of viral polyproteins and thereby stopping the formation of mature, infectious virions.
Atazanavir: It is an azapeptide HIV-1 protease inhibitor that blocks viral maturation by selectively inhibiting the cleavage of Gag and Gag-Pol polyproteins in HIV-1–infected cells, preventing the formation of infectious virions.
Darunavir: It is an HIV-1 protease inhibitor that blocks cleavage of the viral Gag-Pol polyprotein in infected cells. It prevents the formation of mature and infectious virus particles. It is used for HIV infection resistant to other antiretroviral therapies and is typically coadministered with low-dose ritonavir to enhance its blood levels.
Fosamprenavir: It is a prodrug which convert to amprenavir by cellular phosphatases in-vivo.
Lopinavir and ritonavir: Lopinavir is an HIV protease inhibitor that prevents the enzyme from processing viral polyproteins, resulting in noninfectious, immature HIV particles. It is commonly combined with ritonavir which inhibits lopinavir’s metabolism by CYP3A and increasing the plasma concentration and effectiveness.
Nelfinavir: It is a protease inhibitor that blocks HIV-1 protease activity and lead to the formation of immature, noninfectious viral particles.
Ritonavir: It is a protease inhibitor which is used in combination with nucleoside analogs and other protease inhibitors as part of double or triple ART.
Tipranavir: It is a nonpeptidic protease inhibitor used in combination antiretroviral therapy for adults with HIV-1 who have ongoing viral replication and resistance to multiple protease inhibitors. It must be coadministered with ritonavir to achieve effective drug levels, and its use should be guided by resistance testing and treatment history.
Use of Antiretroviral agent, non-nucleoside reverse-transcriptase inhibitor
Delavirdine: It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV-1 that binds directly to the viral reverse transcriptase enzyme, blocking both RNA- and DNA-dependent DNA polymerase activities and thereby inhibiting viral replication.
Efavirenz: It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) effective against HIV-1 infection. It binds to reverse transcriptase, inhibiting both RNA- and DNA-dependent DNA polymerase activities to block viral replication, and unlike NRTIs, it does not require intracellular phosphorylation to be active.
Etravirine: It is an NNRTI for HIV-1 that binds directly to reverse transcriptase, disrupting its catalytic site and inhibiting RNA- and DNA-dependent DNA polymerase activities, while sparing human DNA polymerases α, β, and γ. It is used in combination with other antiretroviral agents for treatment-experienced adults with ongoing viral replication and HIV-1 strains resistant to NNRTIs or other antiretrovirals. It should not be combined solely with NRTIs in patients with prior NNRTI virologic failure.
Nevirapine: It is an NNRTI that inhibits HIV replication by nucleoside reverse transcriptase inhibitors like zidovudine and lamivudine.
Rilpivirine: It is an NNRTI that suppresses HIV-1 replication via noncompetitive inhibition of HIV-1 reverse transcriptase, without affecting human DNA polymerases alpha, beta, or gamma.
Doravirine: It is used in combination with other antiretroviral agents for treating HIV-1 in adults who are either ART-naĂŻve or virologically suppressed on a stable regimen (HIV-1 RNA <50 copies/mL) with no prior treatment failure or known resistance to doravirine.
Use of Antiretroviral Agent, Integrase Inhibitor
It is an antiretroviral agent that blocks the integration of viral DNA into the host genome and is indicated for combination therapy in treatment-experienced adults with ongoing viral replication and HIV-1 strains resistant to other drugs.
Raltegravir: It is an integrase strand transfer inhibitor (INSTI) class drug. It used to block integration of HIV DNA into host cells.
Dolutegravir: It is INSTI that blocks the catalytic activity of HIV-1 integrase and prevents the viral DNA from integrating into host DNA. It is approved for children aged ≥12 years weighing at least 40 kg.
Elvitegravir: It is an integrase inhibitor used alongside an HIV protease inhibitor (such as atazanavir, lopinavir, darunavir, fosamprenavir, or tipranavir) and ritonavir, in combination with other antiretrovirals for treating HIV-1 in treatment-experienced adults.
Cabotegravir: Oral cabotegravir is indicated in combination with rilpivirine as a complete short-term HIV-1 regimen for adults who are virologically suppressed on stable ART, with no history of treatment failure or resistance to either drug. It serves as lead-in therapy for Cabenuva (cabotegravir IM + rilpivirine IM), for temporary replacement during missed injections, and is also approved as an injectable PrEP every 2 months in adolescents and adults weighing ≥35 kg.
Use of Antiretroviral agent, CCR5 antagonist
CCR5 antagonists prevent the HIV by entering in white blood cells and blcoks the CCR5 co-receptor on the cell surface.
Maraviroc: Maraviroc is a CCR5 antagonist that prevents HIV-1 (R5-tropic) from entering white blood cells and reduces the viral load and boosting T-cell counts. It is FDA-approved for use in combination with optimized therapy for treatment-experienced adults with R5-only virus and multi-drug resistant HIV-1.
Use of HIV, Entry Inhibitors
It is an HIV entry inhibitor approved based on the MB-301 phase 3 trial, which evaluated treatment-experienced patients with multidrug-resistant HIV-1. At 24 weeks, 43% of participants got the viral suppression below 50 copies/mL with greater responses in those with baseline CD4 counts above 50 cells/µL. The mean CD4 gain was 48 cells/µL overall, with higher gains in patients starting above 50 cells/µL, and substantial reductions in HIV RNA levels were observed across the cohort.
Ibalizumab: It is a CD4-directed post-attachment inhibitor that blocks HIV entry and fusion into CD4 cells. While it does not prevent gp120 from binding CD4, it induces conformational changes that stop the gp120-CD4 complex from interacting with CCR5 or CXCR4, thereby preventing viral entry while maintaining normal immune function. It is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 and is used alongside the patient’s existing ART regimen.
Use of HIV, Attachment Inhibitors
HIV-1 attachment inhibitors reduce the viral replication by attaching directly to glycoprotein 120 (gp120) subunit on surface of the virus.
Fostemsavir: It is a prodrug of temsavir and a first-in-class HIV-1 attachment inhibitor. It binds to viral gp120 subunit and prevents the HIV from attachment to CD4+ T cells and other immune cells. It is indicated for use with other antiretrovirals in heavily treatment-experienced adults with multidrug-resistant HIV-1 who are failing their current ART due to resistance, intolerance, or safety concerns.
Use of Capsid Inhibitors
Capsid inhibitor binds directly to HIV-1 capsid protein (p24) hexamers, disrupting multiple stages of the viral lifecycle, including nuclear import of proviral DNA, virus assembly and release, and proper capsid core formation. Its approval was supported by the Phase 2/3 CAPELLA trial, in which 81–83% of participants with multidrug-resistant HIV-1 achieved viral loads below 50 copies/mL at week 26 when lenacapavir was combined with an optimized background regimen.
Lenacapavir: It is a first-in-class capsid inhibitor administered twice yearly. It is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection and is also approved for PrEP in adolescents and adults weighing at least 35 kg (77 pounds).
Use of Complete Regimen Combinations
Fixed-dose combination regimens simplify HIV treatment by reducing the number of pills and dosing frequency, thereby improving patient adherence. Two-, three-, and four-drug combinations are available to achieve this.
Cabotegravir/rilpivirine: Monthly injectable regimen for adults with HIV-1 who are virologically suppressed, replacing a stable ART regimen. Initiated after a 30-day oral lead-in with the same drugs to ensure safety and tolerance.
Dolutegravir/rilpivirine: Dolutegravir and rilpivirine form the first 2-drug, fixed-dose regimen approved for HIV-1, indicated for adults who are virologically suppressed on a stable ART regimen for at least 6 months with no history of treatment failure or known resistance.
Dolutegravir/lamivudine: Dolutegravir/lamivudine is a first 2-drug, fixed-dose regimen for treatment-naïve adults and adolescents (≥12 years, ≥25 kg) with HIV-1, combining an integrase inhibitor and an NRTI, for patients without known resistance to either drug.
Elvitegravir/cobicistat/emtricitabine/tenofovir AF: Genvoya is a once-daily antiretroviral combination tablet for treatment-naïve adults and adolescents (≥12 years) or as a replacement regimen in virologically suppressed patients. It contains elvitegravir (INSTI), emtricitabine and tenofovir AF (NRTIs) and cobicistat as a pharmacokinetic booster.
Darunavir/cobicistat/emtricitabine/tenofovir AF: Darunavir/cobicistat/emtricitabine/tenofovir AF is a once-daily, complete antiretroviral regimen for adults and adolescents (≥40 kg) with HIV-1 infection, suitable for treatment-naïve patients or those virologically suppressed on a stable ART regimen, with no known resistance to darunavir or tenofovir.
Emtricitabine/rilpivirine/tenofovir AF: Emtricitabine/rilpivirine/tenofovir AF is a once-daily, complete antiretroviral regimen for treatment-naïve adults and adolescents (≥12 years) or for virologically suppressed patients on a stable ART regimen, containing one NNRTI (rilpivirine) and two NRTIs (emtricitabine and tenofovir AF).
Elvitegravir/cobicistat/emtricitabine/tenofovir DF: Elvitegravir/cobicistat/emtricitabine/tenofovir DF is a once-daily, complete antiretroviral regimen for treatment-naïve adults, combining an integrase inhibitor (elvitegravir), two NRTIs (emtricitabine and tenofovir DF), and cobicistat, a CYP3A4 booster that enhances elvitegravir’s bioavailability and prolongs its half-life.
Emtricitabine/rilpivirine/tenofovir DF: Emtricitabine/rilpivirine/tenofovir DF is a complete once-daily regimen containing two NRTIs and one NNRTI, indicated for treatment-naïve HIV-1 patients aged ≥12 years with HIV-1 RNA ≤100,000 copies/mL, or for virologically suppressed patients on a stable ART regimen to replace their current therapy.
Bictegravir/emtricitabine/tenofovir AF: It is a three-drug complete regimen combining an integrase inhibitor (bictegravir) with two NRTIs (emtricitabine and tenofovir alafenamide). It is indicated to treat HIV-1 in ART-naïve adults and pediatric patients ≥25 kg or to replace a stable regimen in virologically suppressed patients without resistance to any component.
Efavirenz/lamivudine/tenofovir DF: It is a three-drug regimen in combination of one NNRTI (efavirenz) with two NRTIs (lamivudine and tenofovir DF). It is indicated to treat HIV-1 infection in adults and children who have ≥35 to 40 kg weight.
Doravirine/lamivudine/tenofovir DF: It is a once-daily, three-drug regimen to treate HIV-1 infection. It is indicated for treatment-naĂŻve adults or as a replacement therapy in virologically suppressed patients on a stable ART regimen with no history of treatment failure or known drug resistance.
Use of Antiretroviral Combinations
Abacavir/dolutegravir/lamivudine: It is a fixed-dosage combination drug. It contains two NRTIs (abacavir 600 mg and lamivudine 300 mg) and an integrase strand transfer inhibitor (dolutegravir 50 mg). Dose adjustment of dolutegravir may be needed when used with strong CYP3A4 inducers, typically by adding a single evening dose of dolutegravir.
Emtricitabine/tenofovir DF/efavirenz: It is a NNRTI and NRTI combination product which is used to treat HIV infection.
Emtricitabine/tenofovir DF: A combination of two NRTIs used with other ART agents for treating HIV-1 infection in adults and children ≥17 kg who can swallow tablets. Also approved for pre-exposure prophylaxis (PrEP) in high-risk adults and adolescents, including MSM, serodiscordant couples, IV drug users and other populations at increased risk of the HIV-1 infection.
Emtricitabine/tenofovir AF: It is used with other ART agents to treat HIV-1 infection in adults and adolescents ≥12 years. It is approved for sexual pre-exposure prophylaxis (PrEP) in at-risk adults and adolescents excluding those at risk via receptive vaginal sex.
Lamivudine/tenofovir DF: It is indicated for the usage with other antiretroviral agents to treat HIV-1 infection in adults and children who have ≥35 kg weight.
Darunavir/cobicistat: It is used as part of antiretroviral therapy for HIV-1 infection in adults and children whose age is ≥6 years and weigh at least 25 kg.
Use of CYP3A4 Inhibitors
Ritonavir and cobicistat are used in ART regimens to inhibit CYP3A-mediated metabolism of antiretroviral drugs, increasing their systemic levels and enhancing antiviral efficacy.
Cobicistat: It is a CYP3A inhibitor which is used to boost the systemic exposure of specific antiretrovirals like atazanavir or darunavir when it is given once daily with other ART agents.
Use of Antibiotic, Sulfonamide Derivative
Antimicrobial therapy should be broad enough to target all pathogens that are likely to be present in the given clinical scenario.
Sulfamethoxazole and Trimethoprim: It blocks the synthesis of dihydrofolic acid and inhibits the bacterial growth.
Use of Growth hormone releasing factor
It reduces the visceral adipose tissue.
Tesamorelin: It is a growth hormone–releasing factor (GRF) analog, stimulates growth hormone and IGF-1 production, promoting anabolic and lipolytic effects, and is indicated for reducing excess abdominal fat in patients with HIV-associated lipodystrophy.
by Stage
by Modality
Chemotherapy
Radiation Therapy
Surgical Interventions
Hormone Therapy
Immunotherapy
Hyperthermia
Photodynamic Therapy
Stem Cell Transplant
Targeted Therapy
Palliative Care
Medication
Future Trends
HIV was first recognized in 1981 in the United States when groups of young men showed up with unusual infections like Pneumocystis pneumonia and Kaposi sarcoma. These conditions are typically associated with severe immune deficiency. Researchers identified the virus in 1983 and since then more than 40 million people have died worldwide.
HIV is spread through sexual contact, shared needles and from mother to child. The patterns of transmission vary by region. Hepatitis B, hepatitis C and human herpesvirus 8 co-infections are common. HIV-1 is common and aggressive strain of the virus. HIV-2 is primarily found in West Africa, progresses more slowly and is more difficult to spread.
HIV’s origins come from cross-species transfer from primates in Africa after which the virus spread quickly along trade routes. Stigma, misinformation and political denial worsened the epidemic. These factors discouraged testing and delayed treatment even when effective therapies became available.
HIV is manageable and allows to livelong because of advancements in antiretroviral therapy (ART), prevention and diagnosis. About 39 million people had HIV by 2022, with two-thirds of those individuals living in Africa. This indicates continued transmission as well as increased survival. ART can save lives but it has potential side effects, requires lifelong commitment and does not cure HIV. High costs are incurred by patients and healthcare systems as a result of the epidemic, and obstacles such as stigma, restricted access to care, and financial constraints still prevent universal treatment.
The WHO and UNAIDS are two international health organizations have set aggressive 95-95-95 goals. By 2025, 95% of people with HIV should be aware of their status, 95% of those who have been diagnosed should be taking antiretroviral therapy, and 95% of patients who have received treatment should have viral suppression. Reaching these goals relies not only on medical progress but also on supportive social and policy environments, integration of HIV services with other healthcare needs and community-driven efforts to increase access and fight discrimination.
HIV is a major global health concern. HIV-1 causes the majority of infections and HIV-2 contributes a small fraction. In 2022, 39 million people were living with HIV globally mainly in Sub-Saharan Africa. Global trends show progress specifically in eastern and southern Africa where new infections and AIDS-related deaths have decreased to 50% till 2010. HIV incidence has increased significantly in the Middle East, North Africa, Eastern Europe and Central Asia areas because of stigma, weak health systems and conflict.
Gender disparities in the HIV epidemiology are pronounced with women have the majority of new infections globally. Addressing these disparities is essential to reducing new transmissions. The UNAIDS and WHO identify five populations at highest risk which include men who have sex with men, sex workers, incarcerated individuals, people who inject drugs and transgender or gender-diverse persons. Most transmissions occur through sexual contact, with heterosexual spread dominating in Africa and same-sex transmission more common in many other regions.
HIV is part of the Retroviridae family. This family is unique because its RNA genome changes into DNA before it integrates into the host’s genome. This process leads to lifelong infection. HIV-1 is the well-known and prevalent of two primary species. HIV-2 spreads more slowly and is primarily found in West Africa. Since these cells express the CD4 receptor, the primary site for viral entry, CD4+ T lymphocytes and macrophages are the primary targets of both viruses. By attaching to CD4 and the chemokine co-receptors CCR5 or CXCR4, the viral envelope glycoproteins facilitate this..
Once inside, the HIV-1 capsid usually stays intact until it reaches the nuclear pore complex. Recent studies show that reverse transcription happens in or just after nuclear import. This challenges older ideas that this process took place in the cytoplasm. The viral reverse transcriptase enzyme starts DNA synthesis using host transfer RNA as a primer. HIV is a viral infection caused by a negative-sense DNA strand that is used to create complementary DNA, forming a double-stranded viral genome. The viral integrase inserts this DNA into the host’s chromatin, establishing a proviral state. The viral genome serves as a template for new virions and lead to infection. HIV is found in lymph nodes in two days of mucosal exposure and systemic plasma viremia usually appears within three days. Genetic variability is a key feature of HIV pathogenesis and a significant challenge in treatment. The viral reverse transcriptase has an error rate 100 to 1,000 times higher than cellular DNA polymerases, leading to frequent point mutations.
HIV also disrupts humoral immunity, especially within B-cell follicles. Follicular helper and regulatory T cells, along with the limited presence of follicular CD8+ cytotoxic T cells, lead to weak antibody responses and the survival of viral reservoirs. These immune sanctuaries persist in patients receiving ART, making viral eradication particularly difficult.
HIV is part of the Retroviridae family and the Lentivirus genus. It mainly infects CD4+ T-helper lymphocytes, which leads to gradual immune suppression. This can weaken the body’s defense system and make people more susceptible to opportunistic infection. If untreated, the infection progresses to AIDS. This stage is characterized by severe immunodeficiency and serious health issues.
HIV-1 and HIV-2 are the two primary types of the virus. Each variety originates from distinct simian immunodeficiency virus transmissions across species. HIV-1 and HIV-2 are different in terms of their severity, ease of transmission and health consequences. Only roughly 48% of the nucleotide sequences and 60% of the amino acid sequences of HIV-1 and HIV-2 are similar on a molecular level.
A conical protein capsid is encased in a lipid envelope in both virus types. Important viral enzymes like reverse transcriptase, integrase and nucleocapsid proteins are present in this capsid along with two identical RNA genomes. Contact with infected bodily fluids like blood, semen, vaginal and rectal secretions, breast milk and amniotic fluid can spread virus. Unprotected sex, mother-to-child transmission during pregnancy or delivery and sharing contaminated syringes or medical equipment are common ways of transmission.
HIV infection is fatal without treatment. The effective antiretroviral therapy (ART) has transformed prognosis. Sustained virologic suppression with ART significantly improves survival, with life expectancy varying by age of initiation and regional resources. A 2017 meta-analysis estimated that starting ART at age 20 confers an average life expectancy of 43.3 years in high-income countries and 28.3 years in low- and middle-income regions. Delayed initiation at age 35 reduces this to 32.2 and 25.6 years, respectively. These gains reflect advances in therapy, earlier treatment initiation, and improved adherence and socioeconomic support.
The most critical determinant of outcome is durable viral suppression. Patients who maintain viral suppression but fail to achieve immunologic recovery (CD4+ <200 cells/mmÂł) experience a 2.6-fold higher risk of all-cause mortality compared with those whose CD4+ counts recover. Initiating ART at the time of diagnosis improves immune reconstitution and clinical outcomes, whereas delaying therapy until CD4+ levels fall below 200 cells/mmÂł markedly reduces the chance of full immune recovery and increases AIDS and non-AIDS morbidity.
History
When evaluating patients with confirmed or suspected HIV, a thorough medical history is crucial. In order to find symptoms that could indicate opportunistic infections or HIV-related complications, this process combines a review of systems with focused questioning. Finding coexisting conditions and staging the infection are further benefits of a thorough history.
Risk factor assessment is critical and should be approached in a nonjudgmental manner. Sexual history including the number of partners, sexual behaviors, use of barrier protection and history of STIs and knowledge of partner’s HIV status are important components. The kind of drug, how often it is used, how it is administered, and whether injection supplies are shared should all be included in a substance use history. Additionally, a history of blood transfusions should be documented.
Because depression, mental illness and substance use disorders can make it difficult to stick with therapy, mental health screening is essential. To find gaps in vaccine-preventable disease coverage, vaccination history should be examined. This is especially important for pneumococcal and hepatitis B infections, which are serious risks for individuals with HIV. Living conditions, support networks, money, insurance, stigma, coping mechanisms and possible exposure to violence are all examined in social history since they have an impact on adherence and care access.
Staging frameworks provide context for disease progression. The U.S. NIH describes acute HIV, chronic HIV, and AIDS as sequential stages, while the CDC uses a classification system based on CD4+ counts and AIDS-defining illnesses. The WHO additionally employs a staging method relying on clinical presentation in areas with limited CD4+ testing.
The physical examination in patients who have HIV focuses on identify the findings that correlate with the stage of infection and possible opportunistic diseases.
AIDS: In advanced disease, physical findings reflect opportunistic infection and malignancies, including pulmonary or gastrointestinal candidiasis, invasive cervical cancer, cryptococcal meningitis, cytomegalovirus retinitis, Kaposi sarcoma, tuberculosis, HIV encephalopathy, non-Hodgkin and Burkitt lymphomas, Pneumocystis jirovecii pneumonia, progressive multifocal leukoencephalopathy, Salmonella septicemia, and HIV-associated wasting. These are linked to profound immunosuppression typically with CD4+ counts below 200 cells/mmÂł.
HIV must be considered in patient who have recurrent severe infection. Other diseases which can have same effects on immune system of patients are:
Severe combined immune deficiency syndrome
Severe malnutrition
Chemotherapy induced immunosuppression
The differential diagnosis in patient who have acute HIV are:
Systemic lupus erythematosus (SLE)
Viral hepatitis
Toxoplasmosis
Mononucleosis
HIV treatment aims to prevent the immune system deterioration and reduce the risk of opportunistic infections, AIDS-defining illnesses and non-AIDS-related complications. It improves the survival and quality of life by restoring the immune function, suppressing viral replication and decreasing HIV-related morbidity. Highly active antiretroviral therapy (HAART) along with combined antiretroviral therapy (ART) is the cornerstone of management. Effective treatment reduces the risk of immune reconstitution inflammatory syndrome (IRIS), improves CD4 T-cell recovery and partially restores immune repertoire. Long-term use of HAART reduces psychiatric and renal comorbidities, but risks may persist.
Antiretroviral Therapy (ART)
Classes of antiretroviral drugs include:
ART is prescribed in combination regimens, usually consisting of two NRTIs plus an agent from another class, most often an INSTI. Treatment must be individualized on the basis of viral load, CD4 count, comorbid conditions, drug resistance profile, potential side effects, pill burden and drug–drug interactions.
Two major guideline sources the U.S. Department of Health and Human Services (DHHS) and the International AIDS Society–USA Panel (IAS-USA) provide updated treatment standards. Both recommend early and universal initiation of ART for all patients with HIV, regardless of CD4 count, with “rapid start” favored where possible.
Historically, ART was delayed until CD4 counts fell below 200 cells/µL. However, multiple cohort studies and clinical trials including the NIH CIPRA HT 001 study demonstrated improved survival, reduced tuberculosis incidence, and lower overall mortality when ART was initiated earlier (CD4 200–350 cells/µL). Modern practice now supports immediate ART initiation at diagnosis, unless contraindicated by acute opportunistic infections.
Rapid ART start: Trials in Lesotho, Haiti, and South Africa demonstrated improved virologic suppression and patient retention with same-day initiation. U.S. programs in San Francisco and New York City have successfully implemented rapid-start protocols, achieving shorter times to viral suppression and improved linkage to care. Rapid start is recommended in all patients who are clinically ready and without contraindications.
Recent trials show that INSTI-based regimens are superior to older NNRTI-based regimens with higher suppression rates and fewer adverse effects. Dolutegravir and bictegravir are now first-line because of their potency, tolerability and resistance barriers. Studies have showed that  raltegravir and dolutegravir have better virologic suppression and fewer side effects compared to efavirenz. Fixed-dose combinations and newer formulations improve adherence through single-tablet regimens. Short-course ART combined with single-dose nevirapine reduces vertical transmission and minimizes resistance development in pregnancy.
Use of Prophylaxis for Opportunistic Infections
The prevention of opportunistic infection is a necessary in HIV care specifically in patients who have severe immunosuppression. Pneumocystis jirovecii pneumonia (PCP) is the common and avoidable consequence. Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is recommended when CD4 count falls below 200/µL. If immune recovery occurs and CD4 counts remain above 200/µL with effective ART, PCP prophylaxis can be safely discontinued. In patients unable to tolerate TMP-SMX, alternatives include dapsone (following G6PD deficiency screening), atovaquone, or monthly inhaled pentamidine.
Because TMP-SMX also protects against toxoplasmosis, it should be initiated in patients with CD4 counts below 100/µL if not already prescribed for PCP prevention.
When CD4 counts decline to <50/µL, the risk of Mycobacterium avium complex (MAC) infection increases. Weekly azithromycin or clarithromycin is effective prophylaxis, though recent evidence suggests that routine primary prophylaxis is unnecessary in patients on suppressive ART due to markedly reduced incidence and mortality.
Routine prophylaxis against fungal or viral infections is not generally recommended. However, fluconazole may be considered for patients with very low CD4 counts (<50/µL) in areas with high rates of histoplasmosis or coccidioidomycosis, although its use raises concerns about drug resistance, especially in Candida species.
For cytomegalovirus (CMV), oral ganciclovir has been shown to lower the risk of invasive disease by about 50% in advanced AIDS. Nonetheless, due to potential resistance, it should be reserved for patients with CD4 counts below 50/µL who also have evidence of prior CMV infection.
Treatment of HIV-Associated Lipodystrophy
HIV-associated lipodystrophy is characterized by either central fat gain or regional fat loss in individuals on antiretroviral treatment. To address this issue, the FDA authorized tesamorelin (Egrifta) in 2010 to reduce extra visceral belly fat in patients.
The results of two major, multicenter, phase III, randomized, double-blind, placebo-controlled studies supported the approval. These investigations, which included approximately 800 HIV-infected individuals with abdominal fat buildup, included two phases: a 26-week therapy phase and a 26-week extension phase. Tesamorelin dramatically decreased visceral adipose tissue by week 26, and the benefits persisted until week 52. Decreases in abdominal fat were associated with improvements in metabolic parameters such as cholesterol and glucose management, emphasizing the therapeutic effects for both body composition and metabolism.
Suppressive Therapy for Herpes Simplex Virus 2 Infection
Co-infection with herpes simplex virus type 2 (HSV-2) is widespread among HIV-1 patients. Acyclovir-based suppressive treatment has been proven in studies to reduce plasma HIV-1 levels and moderately impede progression.
In a large, randomized study involving 3,381 HIV-1/HSV-2 coinfected patients who were not yet on antiretroviral therapy and had CD4 counts ≥250/μL, acyclovir (400 mg orally twice daily) reduced the overall risk of HIV-1 progression by 16% compared with placebo. Progression was defined as the first decline in CD4 T-cell counts below 200/μL.
Notably, among participants with baseline CD4 counts ≥350/μL, acyclovir use delayed the decline to below 350/μL by 19%, suggesting potential benefit in early disease stages. These findings highlight acyclovir’s role in modifying HIV-1 dynamics through HSV-2 suppression. However, further investigation is needed to clarify whether acyclovir prophylaxis prior to starting ART provides long-term benefit in slowing HIV progression.
Management of HIV-Associated Diarrhea
Diarrhea is a common consequence of HIV/AIDS, especially in people undergoing antiretroviral medication (ART). To address this, the US Food and Drug Administration (FDA) authorized rofelemer in December 2012 as a treatment alternative for symptom reduction in these individuals.
Before initiating rofelemer, it is essential to rule out secondary causes, including infectious pathogens or underlying gastrointestinal diseases, since targeted management of these conditions may be required. Once other etiologies are excluded, rofelemer provides a safe and effective means to reduce diarrhea, thereby improving quality of life and adherence to ART regimens.
Medication
Use of Antiretroviral Therapy (ART) in HIV Infection
Importance of ART
Effective antiretroviral therapy (ART) remains the cornerstone of HIV management, as it significantly improves survival, enhances quality of life, and prevents opportunistic infections. Standard therapy involves combinations of antiretroviral drugs, selected according to established guidelines, and tailored to patient-specific factors such as prior treatment exposure, comorbidities (e.g., hepatitis C coinfection), and drug resistance patterns.
Antiretroviral Drug Classes
ART agents fall into multiple pharmacologic categories, each targeting distinct steps in the viral replication cycle:
Combination Therapy and Resistance
Combination ART, often termed highly active ART (HAART), is the standard of care because:
Ritonavir is now primarily used as a pharmacokinetic booster. It enhances the bioavailability of coadministered protease inhibitors.
Fixed-Dose Combination Products
To improve adherence and simplify regimens, numerous once-daily fixed-dose combinations are available, such as:
These regimens reduce pill burden, improve compliance, and maintain viral suppression with fewer side effects.
Clinical Trial Evidence for Regimen Effectiveness
Pediatric Considerations
Several ART drugs initially approved for adults/adolescents are now FDA-approved for children, with dosing adjustments. New formulations like tenofovir alafenamide (TAF) are preferred because of improved renal and bone safety compared with tenofovir DF.
Use of Antiretroviral agent, nucleoside reverse-transcriptase inhibitor
NRTIs agents inhibit the viral replication by suppressing viral RNA dependent DNA polymerase.
Abacavir (Ziagen): It is an NRTI which inhibits HIV viral replication by blocking the RNA-dependent DNA polymerase. Patients should be screened for HLA-B*5701 before starting the treatment to reduce the risk of hypersensitivity reactions.
Didanosine: It interferes with the HIV viral RNA dependent DNA polymerase and inhibits the viral replication.
Emtricitabine: It is a synthetic nucleoside cytosine analog. It works by competing with deoxycytidine-5′-triphosphate, incorporating into viral DNA, and causing chain termination to inhibit HIV replication.
Lamivudine: It is a thymidine agent which inhibits the viral replication.
Tenofovir disoproxil fumarate (TDF): It is a prodrug that inhibits HIV reverse transcriptase. It is competing with deoxyadenosine 5′-triphosphate and causing DNA chain termination. It is converted to tenofovir in the body, has enhanced bioavailability with high-fat meals, allows once-daily dosing, and has demonstrated efficacy in PrEP trials for IV drug users and heterosexually active adults, though its use is not recommended for MSM.
Zidovudine (Retrovir): It is a thymidine analog which inhibits the HIV replication by interfering with viral DNA synthesis.
Use of Antiretroviral Agent, Protease Inhibitor
Protease Inhibitors (PIs) block HIV protease, preventing cleavage of viral polyproteins and thereby stopping the formation of mature, infectious virions.
Atazanavir: It is an azapeptide HIV-1 protease inhibitor that blocks viral maturation by selectively inhibiting the cleavage of Gag and Gag-Pol polyproteins in HIV-1–infected cells, preventing the formation of infectious virions.
Darunavir: It is an HIV-1 protease inhibitor that blocks cleavage of the viral Gag-Pol polyprotein in infected cells. It prevents the formation of mature and infectious virus particles. It is used for HIV infection resistant to other antiretroviral therapies and is typically coadministered with low-dose ritonavir to enhance its blood levels.
Fosamprenavir: It is a prodrug which convert to amprenavir by cellular phosphatases in-vivo.
Lopinavir and ritonavir: Lopinavir is an HIV protease inhibitor that prevents the enzyme from processing viral polyproteins, resulting in noninfectious, immature HIV particles. It is commonly combined with ritonavir which inhibits lopinavir’s metabolism by CYP3A and increasing the plasma concentration and effectiveness.
Nelfinavir: It is a protease inhibitor that blocks HIV-1 protease activity and lead to the formation of immature, noninfectious viral particles.
Ritonavir: It is a protease inhibitor which is used in combination with nucleoside analogs and other protease inhibitors as part of double or triple ART.
Tipranavir: It is a nonpeptidic protease inhibitor used in combination antiretroviral therapy for adults with HIV-1 who have ongoing viral replication and resistance to multiple protease inhibitors. It must be coadministered with ritonavir to achieve effective drug levels, and its use should be guided by resistance testing and treatment history.
Use of Antiretroviral agent, non-nucleoside reverse-transcriptase inhibitor
Delavirdine: It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV-1 that binds directly to the viral reverse transcriptase enzyme, blocking both RNA- and DNA-dependent DNA polymerase activities and thereby inhibiting viral replication.
Efavirenz: It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) effective against HIV-1 infection. It binds to reverse transcriptase, inhibiting both RNA- and DNA-dependent DNA polymerase activities to block viral replication, and unlike NRTIs, it does not require intracellular phosphorylation to be active.
Etravirine: It is an NNRTI for HIV-1 that binds directly to reverse transcriptase, disrupting its catalytic site and inhibiting RNA- and DNA-dependent DNA polymerase activities, while sparing human DNA polymerases α, β, and γ. It is used in combination with other antiretroviral agents for treatment-experienced adults with ongoing viral replication and HIV-1 strains resistant to NNRTIs or other antiretrovirals. It should not be combined solely with NRTIs in patients with prior NNRTI virologic failure.
Nevirapine: It is an NNRTI that inhibits HIV replication by nucleoside reverse transcriptase inhibitors like zidovudine and lamivudine.
Rilpivirine: It is an NNRTI that suppresses HIV-1 replication via noncompetitive inhibition of HIV-1 reverse transcriptase, without affecting human DNA polymerases alpha, beta, or gamma.
Doravirine: It is used in combination with other antiretroviral agents for treating HIV-1 in adults who are either ART-naĂŻve or virologically suppressed on a stable regimen (HIV-1 RNA <50 copies/mL) with no prior treatment failure or known resistance to doravirine.
Use of Antiretroviral Agent, Integrase Inhibitor
It is an antiretroviral agent that blocks the integration of viral DNA into the host genome and is indicated for combination therapy in treatment-experienced adults with ongoing viral replication and HIV-1 strains resistant to other drugs.
Raltegravir: It is an integrase strand transfer inhibitor (INSTI) class drug. It used to block integration of HIV DNA into host cells.
Dolutegravir: It is INSTI that blocks the catalytic activity of HIV-1 integrase and prevents the viral DNA from integrating into host DNA. It is approved for children aged ≥12 years weighing at least 40 kg.
Elvitegravir: It is an integrase inhibitor used alongside an HIV protease inhibitor (such as atazanavir, lopinavir, darunavir, fosamprenavir, or tipranavir) and ritonavir, in combination with other antiretrovirals for treating HIV-1 in treatment-experienced adults.
Cabotegravir: Oral cabotegravir is indicated in combination with rilpivirine as a complete short-term HIV-1 regimen for adults who are virologically suppressed on stable ART, with no history of treatment failure or resistance to either drug. It serves as lead-in therapy for Cabenuva (cabotegravir IM + rilpivirine IM), for temporary replacement during missed injections, and is also approved as an injectable PrEP every 2 months in adolescents and adults weighing ≥35 kg.
Use of Antiretroviral agent, CCR5 antagonist
CCR5 antagonists prevent the HIV by entering in white blood cells and blcoks the CCR5 co-receptor on the cell surface.
Maraviroc: Maraviroc is a CCR5 antagonist that prevents HIV-1 (R5-tropic) from entering white blood cells and reduces the viral load and boosting T-cell counts. It is FDA-approved for use in combination with optimized therapy for treatment-experienced adults with R5-only virus and multi-drug resistant HIV-1.
Use of HIV, Entry Inhibitors
It is an HIV entry inhibitor approved based on the MB-301 phase 3 trial, which evaluated treatment-experienced patients with multidrug-resistant HIV-1. At 24 weeks, 43% of participants got the viral suppression below 50 copies/mL with greater responses in those with baseline CD4 counts above 50 cells/µL. The mean CD4 gain was 48 cells/µL overall, with higher gains in patients starting above 50 cells/µL, and substantial reductions in HIV RNA levels were observed across the cohort.
Ibalizumab: It is a CD4-directed post-attachment inhibitor that blocks HIV entry and fusion into CD4 cells. While it does not prevent gp120 from binding CD4, it induces conformational changes that stop the gp120-CD4 complex from interacting with CCR5 or CXCR4, thereby preventing viral entry while maintaining normal immune function. It is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 and is used alongside the patient’s existing ART regimen.
Use of HIV, Attachment Inhibitors
HIV-1 attachment inhibitors reduce the viral replication by attaching directly to glycoprotein 120 (gp120) subunit on surface of the virus.
Fostemsavir: It is a prodrug of temsavir and a first-in-class HIV-1 attachment inhibitor. It binds to viral gp120 subunit and prevents the HIV from attachment to CD4+ T cells and other immune cells. It is indicated for use with other antiretrovirals in heavily treatment-experienced adults with multidrug-resistant HIV-1 who are failing their current ART due to resistance, intolerance, or safety concerns.
Use of Capsid Inhibitors
Capsid inhibitor binds directly to HIV-1 capsid protein (p24) hexamers, disrupting multiple stages of the viral lifecycle, including nuclear import of proviral DNA, virus assembly and release, and proper capsid core formation. Its approval was supported by the Phase 2/3 CAPELLA trial, in which 81–83% of participants with multidrug-resistant HIV-1 achieved viral loads below 50 copies/mL at week 26 when lenacapavir was combined with an optimized background regimen.
Lenacapavir: It is a first-in-class capsid inhibitor administered twice yearly. It is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection and is also approved for PrEP in adolescents and adults weighing at least 35 kg (77 pounds).
Use of Complete Regimen Combinations
Fixed-dose combination regimens simplify HIV treatment by reducing the number of pills and dosing frequency, thereby improving patient adherence. Two-, three-, and four-drug combinations are available to achieve this.
Cabotegravir/rilpivirine: Monthly injectable regimen for adults with HIV-1 who are virologically suppressed, replacing a stable ART regimen. Initiated after a 30-day oral lead-in with the same drugs to ensure safety and tolerance.
Dolutegravir/rilpivirine: Dolutegravir and rilpivirine form the first 2-drug, fixed-dose regimen approved for HIV-1, indicated for adults who are virologically suppressed on a stable ART regimen for at least 6 months with no history of treatment failure or known resistance.
Dolutegravir/lamivudine: Dolutegravir/lamivudine is a first 2-drug, fixed-dose regimen for treatment-naïve adults and adolescents (≥12 years, ≥25 kg) with HIV-1, combining an integrase inhibitor and an NRTI, for patients without known resistance to either drug.
Elvitegravir/cobicistat/emtricitabine/tenofovir AF: Genvoya is a once-daily antiretroviral combination tablet for treatment-naïve adults and adolescents (≥12 years) or as a replacement regimen in virologically suppressed patients. It contains elvitegravir (INSTI), emtricitabine and tenofovir AF (NRTIs) and cobicistat as a pharmacokinetic booster.
Darunavir/cobicistat/emtricitabine/tenofovir AF: Darunavir/cobicistat/emtricitabine/tenofovir AF is a once-daily, complete antiretroviral regimen for adults and adolescents (≥40 kg) with HIV-1 infection, suitable for treatment-naïve patients or those virologically suppressed on a stable ART regimen, with no known resistance to darunavir or tenofovir.
Emtricitabine/rilpivirine/tenofovir AF: Emtricitabine/rilpivirine/tenofovir AF is a once-daily, complete antiretroviral regimen for treatment-naïve adults and adolescents (≥12 years) or for virologically suppressed patients on a stable ART regimen, containing one NNRTI (rilpivirine) and two NRTIs (emtricitabine and tenofovir AF).
Elvitegravir/cobicistat/emtricitabine/tenofovir DF: Elvitegravir/cobicistat/emtricitabine/tenofovir DF is a once-daily, complete antiretroviral regimen for treatment-naïve adults, combining an integrase inhibitor (elvitegravir), two NRTIs (emtricitabine and tenofovir DF), and cobicistat, a CYP3A4 booster that enhances elvitegravir’s bioavailability and prolongs its half-life.
Emtricitabine/rilpivirine/tenofovir DF: Emtricitabine/rilpivirine/tenofovir DF is a complete once-daily regimen containing two NRTIs and one NNRTI, indicated for treatment-naïve HIV-1 patients aged ≥12 years with HIV-1 RNA ≤100,000 copies/mL, or for virologically suppressed patients on a stable ART regimen to replace their current therapy.
Bictegravir/emtricitabine/tenofovir AF: It is a three-drug complete regimen combining an integrase inhibitor (bictegravir) with two NRTIs (emtricitabine and tenofovir alafenamide). It is indicated to treat HIV-1 in ART-naïve adults and pediatric patients ≥25 kg or to replace a stable regimen in virologically suppressed patients without resistance to any component.
Efavirenz/lamivudine/tenofovir DF: It is a three-drug regimen in combination of one NNRTI (efavirenz) with two NRTIs (lamivudine and tenofovir DF). It is indicated to treat HIV-1 infection in adults and children who have ≥35 to 40 kg weight.
Doravirine/lamivudine/tenofovir DF: It is a once-daily, three-drug regimen to treate HIV-1 infection. It is indicated for treatment-naĂŻve adults or as a replacement therapy in virologically suppressed patients on a stable ART regimen with no history of treatment failure or known drug resistance.
Use of Antiretroviral Combinations
Abacavir/dolutegravir/lamivudine: It is a fixed-dosage combination drug. It contains two NRTIs (abacavir 600 mg and lamivudine 300 mg) and an integrase strand transfer inhibitor (dolutegravir 50 mg). Dose adjustment of dolutegravir may be needed when used with strong CYP3A4 inducers, typically by adding a single evening dose of dolutegravir.
Emtricitabine/tenofovir DF/efavirenz: It is a NNRTI and NRTI combination product which is used to treat HIV infection.
Emtricitabine/tenofovir DF: A combination of two NRTIs used with other ART agents for treating HIV-1 infection in adults and children ≥17 kg who can swallow tablets. Also approved for pre-exposure prophylaxis (PrEP) in high-risk adults and adolescents, including MSM, serodiscordant couples, IV drug users and other populations at increased risk of the HIV-1 infection.
Emtricitabine/tenofovir AF: It is used with other ART agents to treat HIV-1 infection in adults and adolescents ≥12 years. It is approved for sexual pre-exposure prophylaxis (PrEP) in at-risk adults and adolescents excluding those at risk via receptive vaginal sex.
Lamivudine/tenofovir DF: It is indicated for the usage with other antiretroviral agents to treat HIV-1 infection in adults and children who have ≥35 kg weight.
Darunavir/cobicistat: It is used as part of antiretroviral therapy for HIV-1 infection in adults and children whose age is ≥6 years and weigh at least 25 kg.
Use of CYP3A4 Inhibitors
Ritonavir and cobicistat are used in ART regimens to inhibit CYP3A-mediated metabolism of antiretroviral drugs, increasing their systemic levels and enhancing antiviral efficacy.
Cobicistat: It is a CYP3A inhibitor which is used to boost the systemic exposure of specific antiretrovirals like atazanavir or darunavir when it is given once daily with other ART agents.
Use of Antibiotic, Sulfonamide Derivative
Antimicrobial therapy should be broad enough to target all pathogens that are likely to be present in the given clinical scenario.
Sulfamethoxazole and Trimethoprim: It blocks the synthesis of dihydrofolic acid and inhibits the bacterial growth.
Use of Growth hormone releasing factor
It reduces the visceral adipose tissue.
Tesamorelin: It is a growth hormone–releasing factor (GRF) analog, stimulates growth hormone and IGF-1 production, promoting anabolic and lipolytic effects, and is indicated for reducing excess abdominal fat in patients with HIV-associated lipodystrophy.
HIV was first recognized in 1981 in the United States when groups of young men showed up with unusual infections like Pneumocystis pneumonia and Kaposi sarcoma. These conditions are typically associated with severe immune deficiency. Researchers identified the virus in 1983 and since then more than 40 million people have died worldwide.
HIV is spread through sexual contact, shared needles and from mother to child. The patterns of transmission vary by region. Hepatitis B, hepatitis C and human herpesvirus 8 co-infections are common. HIV-1 is common and aggressive strain of the virus. HIV-2 is primarily found in West Africa, progresses more slowly and is more difficult to spread.
HIV’s origins come from cross-species transfer from primates in Africa after which the virus spread quickly along trade routes. Stigma, misinformation and political denial worsened the epidemic. These factors discouraged testing and delayed treatment even when effective therapies became available.
HIV is manageable and allows to livelong because of advancements in antiretroviral therapy (ART), prevention and diagnosis. About 39 million people had HIV by 2022, with two-thirds of those individuals living in Africa. This indicates continued transmission as well as increased survival. ART can save lives but it has potential side effects, requires lifelong commitment and does not cure HIV. High costs are incurred by patients and healthcare systems as a result of the epidemic, and obstacles such as stigma, restricted access to care, and financial constraints still prevent universal treatment.
The WHO and UNAIDS are two international health organizations have set aggressive 95-95-95 goals. By 2025, 95% of people with HIV should be aware of their status, 95% of those who have been diagnosed should be taking antiretroviral therapy, and 95% of patients who have received treatment should have viral suppression. Reaching these goals relies not only on medical progress but also on supportive social and policy environments, integration of HIV services with other healthcare needs and community-driven efforts to increase access and fight discrimination.
HIV is a major global health concern. HIV-1 causes the majority of infections and HIV-2 contributes a small fraction. In 2022, 39 million people were living with HIV globally mainly in Sub-Saharan Africa. Global trends show progress specifically in eastern and southern Africa where new infections and AIDS-related deaths have decreased to 50% till 2010. HIV incidence has increased significantly in the Middle East, North Africa, Eastern Europe and Central Asia areas because of stigma, weak health systems and conflict.
Gender disparities in the HIV epidemiology are pronounced with women have the majority of new infections globally. Addressing these disparities is essential to reducing new transmissions. The UNAIDS and WHO identify five populations at highest risk which include men who have sex with men, sex workers, incarcerated individuals, people who inject drugs and transgender or gender-diverse persons. Most transmissions occur through sexual contact, with heterosexual spread dominating in Africa and same-sex transmission more common in many other regions.
HIV is part of the Retroviridae family. This family is unique because its RNA genome changes into DNA before it integrates into the host’s genome. This process leads to lifelong infection. HIV-1 is the well-known and prevalent of two primary species. HIV-2 spreads more slowly and is primarily found in West Africa. Since these cells express the CD4 receptor, the primary site for viral entry, CD4+ T lymphocytes and macrophages are the primary targets of both viruses. By attaching to CD4 and the chemokine co-receptors CCR5 or CXCR4, the viral envelope glycoproteins facilitate this..
Once inside, the HIV-1 capsid usually stays intact until it reaches the nuclear pore complex. Recent studies show that reverse transcription happens in or just after nuclear import. This challenges older ideas that this process took place in the cytoplasm. The viral reverse transcriptase enzyme starts DNA synthesis using host transfer RNA as a primer. HIV is a viral infection caused by a negative-sense DNA strand that is used to create complementary DNA, forming a double-stranded viral genome. The viral integrase inserts this DNA into the host’s chromatin, establishing a proviral state. The viral genome serves as a template for new virions and lead to infection. HIV is found in lymph nodes in two days of mucosal exposure and systemic plasma viremia usually appears within three days. Genetic variability is a key feature of HIV pathogenesis and a significant challenge in treatment. The viral reverse transcriptase has an error rate 100 to 1,000 times higher than cellular DNA polymerases, leading to frequent point mutations.
HIV also disrupts humoral immunity, especially within B-cell follicles. Follicular helper and regulatory T cells, along with the limited presence of follicular CD8+ cytotoxic T cells, lead to weak antibody responses and the survival of viral reservoirs. These immune sanctuaries persist in patients receiving ART, making viral eradication particularly difficult.
HIV is part of the Retroviridae family and the Lentivirus genus. It mainly infects CD4+ T-helper lymphocytes, which leads to gradual immune suppression. This can weaken the body’s defense system and make people more susceptible to opportunistic infection. If untreated, the infection progresses to AIDS. This stage is characterized by severe immunodeficiency and serious health issues.
HIV-1 and HIV-2 are the two primary types of the virus. Each variety originates from distinct simian immunodeficiency virus transmissions across species. HIV-1 and HIV-2 are different in terms of their severity, ease of transmission and health consequences. Only roughly 48% of the nucleotide sequences and 60% of the amino acid sequences of HIV-1 and HIV-2 are similar on a molecular level.
A conical protein capsid is encased in a lipid envelope in both virus types. Important viral enzymes like reverse transcriptase, integrase and nucleocapsid proteins are present in this capsid along with two identical RNA genomes. Contact with infected bodily fluids like blood, semen, vaginal and rectal secretions, breast milk and amniotic fluid can spread virus. Unprotected sex, mother-to-child transmission during pregnancy or delivery and sharing contaminated syringes or medical equipment are common ways of transmission.
HIV infection is fatal without treatment. The effective antiretroviral therapy (ART) has transformed prognosis. Sustained virologic suppression with ART significantly improves survival, with life expectancy varying by age of initiation and regional resources. A 2017 meta-analysis estimated that starting ART at age 20 confers an average life expectancy of 43.3 years in high-income countries and 28.3 years in low- and middle-income regions. Delayed initiation at age 35 reduces this to 32.2 and 25.6 years, respectively. These gains reflect advances in therapy, earlier treatment initiation, and improved adherence and socioeconomic support.
The most critical determinant of outcome is durable viral suppression. Patients who maintain viral suppression but fail to achieve immunologic recovery (CD4+ <200 cells/mmÂł) experience a 2.6-fold higher risk of all-cause mortality compared with those whose CD4+ counts recover. Initiating ART at the time of diagnosis improves immune reconstitution and clinical outcomes, whereas delaying therapy until CD4+ levels fall below 200 cells/mmÂł markedly reduces the chance of full immune recovery and increases AIDS and non-AIDS morbidity.
History
When evaluating patients with confirmed or suspected HIV, a thorough medical history is crucial. In order to find symptoms that could indicate opportunistic infections or HIV-related complications, this process combines a review of systems with focused questioning. Finding coexisting conditions and staging the infection are further benefits of a thorough history.
Risk factor assessment is critical and should be approached in a nonjudgmental manner. Sexual history including the number of partners, sexual behaviors, use of barrier protection and history of STIs and knowledge of partner’s HIV status are important components. The kind of drug, how often it is used, how it is administered, and whether injection supplies are shared should all be included in a substance use history. Additionally, a history of blood transfusions should be documented.
Because depression, mental illness and substance use disorders can make it difficult to stick with therapy, mental health screening is essential. To find gaps in vaccine-preventable disease coverage, vaccination history should be examined. This is especially important for pneumococcal and hepatitis B infections, which are serious risks for individuals with HIV. Living conditions, support networks, money, insurance, stigma, coping mechanisms and possible exposure to violence are all examined in social history since they have an impact on adherence and care access.
Staging frameworks provide context for disease progression. The U.S. NIH describes acute HIV, chronic HIV, and AIDS as sequential stages, while the CDC uses a classification system based on CD4+ counts and AIDS-defining illnesses. The WHO additionally employs a staging method relying on clinical presentation in areas with limited CD4+ testing.
The physical examination in patients who have HIV focuses on identify the findings that correlate with the stage of infection and possible opportunistic diseases.
AIDS: In advanced disease, physical findings reflect opportunistic infection and malignancies, including pulmonary or gastrointestinal candidiasis, invasive cervical cancer, cryptococcal meningitis, cytomegalovirus retinitis, Kaposi sarcoma, tuberculosis, HIV encephalopathy, non-Hodgkin and Burkitt lymphomas, Pneumocystis jirovecii pneumonia, progressive multifocal leukoencephalopathy, Salmonella septicemia, and HIV-associated wasting. These are linked to profound immunosuppression typically with CD4+ counts below 200 cells/mmÂł.
HIV must be considered in patient who have recurrent severe infection. Other diseases which can have same effects on immune system of patients are:
Severe combined immune deficiency syndrome
Severe malnutrition
Chemotherapy induced immunosuppression
The differential diagnosis in patient who have acute HIV are:
Systemic lupus erythematosus (SLE)
Viral hepatitis
Toxoplasmosis
Mononucleosis
HIV treatment aims to prevent the immune system deterioration and reduce the risk of opportunistic infections, AIDS-defining illnesses and non-AIDS-related complications. It improves the survival and quality of life by restoring the immune function, suppressing viral replication and decreasing HIV-related morbidity. Highly active antiretroviral therapy (HAART) along with combined antiretroviral therapy (ART) is the cornerstone of management. Effective treatment reduces the risk of immune reconstitution inflammatory syndrome (IRIS), improves CD4 T-cell recovery and partially restores immune repertoire. Long-term use of HAART reduces psychiatric and renal comorbidities, but risks may persist.
Antiretroviral Therapy (ART)
Classes of antiretroviral drugs include:
ART is prescribed in combination regimens, usually consisting of two NRTIs plus an agent from another class, most often an INSTI. Treatment must be individualized on the basis of viral load, CD4 count, comorbid conditions, drug resistance profile, potential side effects, pill burden and drug–drug interactions.
Two major guideline sources the U.S. Department of Health and Human Services (DHHS) and the International AIDS Society–USA Panel (IAS-USA) provide updated treatment standards. Both recommend early and universal initiation of ART for all patients with HIV, regardless of CD4 count, with “rapid start” favored where possible.
Historically, ART was delayed until CD4 counts fell below 200 cells/µL. However, multiple cohort studies and clinical trials including the NIH CIPRA HT 001 study demonstrated improved survival, reduced tuberculosis incidence, and lower overall mortality when ART was initiated earlier (CD4 200–350 cells/µL). Modern practice now supports immediate ART initiation at diagnosis, unless contraindicated by acute opportunistic infections.
Rapid ART start: Trials in Lesotho, Haiti, and South Africa demonstrated improved virologic suppression and patient retention with same-day initiation. U.S. programs in San Francisco and New York City have successfully implemented rapid-start protocols, achieving shorter times to viral suppression and improved linkage to care. Rapid start is recommended in all patients who are clinically ready and without contraindications.
Recent trials show that INSTI-based regimens are superior to older NNRTI-based regimens with higher suppression rates and fewer adverse effects. Dolutegravir and bictegravir are now first-line because of their potency, tolerability and resistance barriers. Studies have showed that  raltegravir and dolutegravir have better virologic suppression and fewer side effects compared to efavirenz. Fixed-dose combinations and newer formulations improve adherence through single-tablet regimens. Short-course ART combined with single-dose nevirapine reduces vertical transmission and minimizes resistance development in pregnancy.
Use of Prophylaxis for Opportunistic Infections
The prevention of opportunistic infection is a necessary in HIV care specifically in patients who have severe immunosuppression. Pneumocystis jirovecii pneumonia (PCP) is the common and avoidable consequence. Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is recommended when CD4 count falls below 200/µL. If immune recovery occurs and CD4 counts remain above 200/µL with effective ART, PCP prophylaxis can be safely discontinued. In patients unable to tolerate TMP-SMX, alternatives include dapsone (following G6PD deficiency screening), atovaquone, or monthly inhaled pentamidine.
Because TMP-SMX also protects against toxoplasmosis, it should be initiated in patients with CD4 counts below 100/µL if not already prescribed for PCP prevention.
When CD4 counts decline to <50/µL, the risk of Mycobacterium avium complex (MAC) infection increases. Weekly azithromycin or clarithromycin is effective prophylaxis, though recent evidence suggests that routine primary prophylaxis is unnecessary in patients on suppressive ART due to markedly reduced incidence and mortality.
Routine prophylaxis against fungal or viral infections is not generally recommended. However, fluconazole may be considered for patients with very low CD4 counts (<50/µL) in areas with high rates of histoplasmosis or coccidioidomycosis, although its use raises concerns about drug resistance, especially in Candida species.
For cytomegalovirus (CMV), oral ganciclovir has been shown to lower the risk of invasive disease by about 50% in advanced AIDS. Nonetheless, due to potential resistance, it should be reserved for patients with CD4 counts below 50/µL who also have evidence of prior CMV infection.
Treatment of HIV-Associated Lipodystrophy
HIV-associated lipodystrophy is characterized by either central fat gain or regional fat loss in individuals on antiretroviral treatment. To address this issue, the FDA authorized tesamorelin (Egrifta) in 2010 to reduce extra visceral belly fat in patients.
The results of two major, multicenter, phase III, randomized, double-blind, placebo-controlled studies supported the approval. These investigations, which included approximately 800 HIV-infected individuals with abdominal fat buildup, included two phases: a 26-week therapy phase and a 26-week extension phase. Tesamorelin dramatically decreased visceral adipose tissue by week 26, and the benefits persisted until week 52. Decreases in abdominal fat were associated with improvements in metabolic parameters such as cholesterol and glucose management, emphasizing the therapeutic effects for both body composition and metabolism.
Suppressive Therapy for Herpes Simplex Virus 2 Infection
Co-infection with herpes simplex virus type 2 (HSV-2) is widespread among HIV-1 patients. Acyclovir-based suppressive treatment has been proven in studies to reduce plasma HIV-1 levels and moderately impede progression.
In a large, randomized study involving 3,381 HIV-1/HSV-2 coinfected patients who were not yet on antiretroviral therapy and had CD4 counts ≥250/μL, acyclovir (400 mg orally twice daily) reduced the overall risk of HIV-1 progression by 16% compared with placebo. Progression was defined as the first decline in CD4 T-cell counts below 200/μL.
Notably, among participants with baseline CD4 counts ≥350/μL, acyclovir use delayed the decline to below 350/μL by 19%, suggesting potential benefit in early disease stages. These findings highlight acyclovir’s role in modifying HIV-1 dynamics through HSV-2 suppression. However, further investigation is needed to clarify whether acyclovir prophylaxis prior to starting ART provides long-term benefit in slowing HIV progression.
Management of HIV-Associated Diarrhea
Diarrhea is a common consequence of HIV/AIDS, especially in people undergoing antiretroviral medication (ART). To address this, the US Food and Drug Administration (FDA) authorized rofelemer in December 2012 as a treatment alternative for symptom reduction in these individuals.
Before initiating rofelemer, it is essential to rule out secondary causes, including infectious pathogens or underlying gastrointestinal diseases, since targeted management of these conditions may be required. Once other etiologies are excluded, rofelemer provides a safe and effective means to reduce diarrhea, thereby improving quality of life and adherence to ART regimens.
Medication
Use of Antiretroviral Therapy (ART) in HIV Infection
Importance of ART
Effective antiretroviral therapy (ART) remains the cornerstone of HIV management, as it significantly improves survival, enhances quality of life, and prevents opportunistic infections. Standard therapy involves combinations of antiretroviral drugs, selected according to established guidelines, and tailored to patient-specific factors such as prior treatment exposure, comorbidities (e.g., hepatitis C coinfection), and drug resistance patterns.
Antiretroviral Drug Classes
ART agents fall into multiple pharmacologic categories, each targeting distinct steps in the viral replication cycle:
Combination Therapy and Resistance
Combination ART, often termed highly active ART (HAART), is the standard of care because:
Ritonavir is now primarily used as a pharmacokinetic booster. It enhances the bioavailability of coadministered protease inhibitors.
Fixed-Dose Combination Products
To improve adherence and simplify regimens, numerous once-daily fixed-dose combinations are available, such as:
These regimens reduce pill burden, improve compliance, and maintain viral suppression with fewer side effects.
Clinical Trial Evidence for Regimen Effectiveness
Pediatric Considerations
Several ART drugs initially approved for adults/adolescents are now FDA-approved for children, with dosing adjustments. New formulations like tenofovir alafenamide (TAF) are preferred because of improved renal and bone safety compared with tenofovir DF.
Use of Antiretroviral agent, nucleoside reverse-transcriptase inhibitor
NRTIs agents inhibit the viral replication by suppressing viral RNA dependent DNA polymerase.
Abacavir (Ziagen): It is an NRTI which inhibits HIV viral replication by blocking the RNA-dependent DNA polymerase. Patients should be screened for HLA-B*5701 before starting the treatment to reduce the risk of hypersensitivity reactions.
Didanosine: It interferes with the HIV viral RNA dependent DNA polymerase and inhibits the viral replication.
Emtricitabine: It is a synthetic nucleoside cytosine analog. It works by competing with deoxycytidine-5′-triphosphate, incorporating into viral DNA, and causing chain termination to inhibit HIV replication.
Lamivudine: It is a thymidine agent which inhibits the viral replication.
Tenofovir disoproxil fumarate (TDF): It is a prodrug that inhibits HIV reverse transcriptase. It is competing with deoxyadenosine 5′-triphosphate and causing DNA chain termination. It is converted to tenofovir in the body, has enhanced bioavailability with high-fat meals, allows once-daily dosing, and has demonstrated efficacy in PrEP trials for IV drug users and heterosexually active adults, though its use is not recommended for MSM.
Zidovudine (Retrovir): It is a thymidine analog which inhibits the HIV replication by interfering with viral DNA synthesis.
Use of Antiretroviral Agent, Protease Inhibitor
Protease Inhibitors (PIs) block HIV protease, preventing cleavage of viral polyproteins and thereby stopping the formation of mature, infectious virions.
Atazanavir: It is an azapeptide HIV-1 protease inhibitor that blocks viral maturation by selectively inhibiting the cleavage of Gag and Gag-Pol polyproteins in HIV-1–infected cells, preventing the formation of infectious virions.
Darunavir: It is an HIV-1 protease inhibitor that blocks cleavage of the viral Gag-Pol polyprotein in infected cells. It prevents the formation of mature and infectious virus particles. It is used for HIV infection resistant to other antiretroviral therapies and is typically coadministered with low-dose ritonavir to enhance its blood levels.
Fosamprenavir: It is a prodrug which convert to amprenavir by cellular phosphatases in-vivo.
Lopinavir and ritonavir: Lopinavir is an HIV protease inhibitor that prevents the enzyme from processing viral polyproteins, resulting in noninfectious, immature HIV particles. It is commonly combined with ritonavir which inhibits lopinavir’s metabolism by CYP3A and increasing the plasma concentration and effectiveness.
Nelfinavir: It is a protease inhibitor that blocks HIV-1 protease activity and lead to the formation of immature, noninfectious viral particles.
Ritonavir: It is a protease inhibitor which is used in combination with nucleoside analogs and other protease inhibitors as part of double or triple ART.
Tipranavir: It is a nonpeptidic protease inhibitor used in combination antiretroviral therapy for adults with HIV-1 who have ongoing viral replication and resistance to multiple protease inhibitors. It must be coadministered with ritonavir to achieve effective drug levels, and its use should be guided by resistance testing and treatment history.
Use of Antiretroviral agent, non-nucleoside reverse-transcriptase inhibitor
Delavirdine: It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV-1 that binds directly to the viral reverse transcriptase enzyme, blocking both RNA- and DNA-dependent DNA polymerase activities and thereby inhibiting viral replication.
Efavirenz: It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) effective against HIV-1 infection. It binds to reverse transcriptase, inhibiting both RNA- and DNA-dependent DNA polymerase activities to block viral replication, and unlike NRTIs, it does not require intracellular phosphorylation to be active.
Etravirine: It is an NNRTI for HIV-1 that binds directly to reverse transcriptase, disrupting its catalytic site and inhibiting RNA- and DNA-dependent DNA polymerase activities, while sparing human DNA polymerases α, β, and γ. It is used in combination with other antiretroviral agents for treatment-experienced adults with ongoing viral replication and HIV-1 strains resistant to NNRTIs or other antiretrovirals. It should not be combined solely with NRTIs in patients with prior NNRTI virologic failure.
Nevirapine: It is an NNRTI that inhibits HIV replication by nucleoside reverse transcriptase inhibitors like zidovudine and lamivudine.
Rilpivirine: It is an NNRTI that suppresses HIV-1 replication via noncompetitive inhibition of HIV-1 reverse transcriptase, without affecting human DNA polymerases alpha, beta, or gamma.
Doravirine: It is used in combination with other antiretroviral agents for treating HIV-1 in adults who are either ART-naĂŻve or virologically suppressed on a stable regimen (HIV-1 RNA <50 copies/mL) with no prior treatment failure or known resistance to doravirine.
Use of Antiretroviral Agent, Integrase Inhibitor
It is an antiretroviral agent that blocks the integration of viral DNA into the host genome and is indicated for combination therapy in treatment-experienced adults with ongoing viral replication and HIV-1 strains resistant to other drugs.
Raltegravir: It is an integrase strand transfer inhibitor (INSTI) class drug. It used to block integration of HIV DNA into host cells.
Dolutegravir: It is INSTI that blocks the catalytic activity of HIV-1 integrase and prevents the viral DNA from integrating into host DNA. It is approved for children aged ≥12 years weighing at least 40 kg.
Elvitegravir: It is an integrase inhibitor used alongside an HIV protease inhibitor (such as atazanavir, lopinavir, darunavir, fosamprenavir, or tipranavir) and ritonavir, in combination with other antiretrovirals for treating HIV-1 in treatment-experienced adults.
Cabotegravir: Oral cabotegravir is indicated in combination with rilpivirine as a complete short-term HIV-1 regimen for adults who are virologically suppressed on stable ART, with no history of treatment failure or resistance to either drug. It serves as lead-in therapy for Cabenuva (cabotegravir IM + rilpivirine IM), for temporary replacement during missed injections, and is also approved as an injectable PrEP every 2 months in adolescents and adults weighing ≥35 kg.
Use of Antiretroviral agent, CCR5 antagonist
CCR5 antagonists prevent the HIV by entering in white blood cells and blcoks the CCR5 co-receptor on the cell surface.
Maraviroc: Maraviroc is a CCR5 antagonist that prevents HIV-1 (R5-tropic) from entering white blood cells and reduces the viral load and boosting T-cell counts. It is FDA-approved for use in combination with optimized therapy for treatment-experienced adults with R5-only virus and multi-drug resistant HIV-1.
Use of HIV, Entry Inhibitors
It is an HIV entry inhibitor approved based on the MB-301 phase 3 trial, which evaluated treatment-experienced patients with multidrug-resistant HIV-1. At 24 weeks, 43% of participants got the viral suppression below 50 copies/mL with greater responses in those with baseline CD4 counts above 50 cells/µL. The mean CD4 gain was 48 cells/µL overall, with higher gains in patients starting above 50 cells/µL, and substantial reductions in HIV RNA levels were observed across the cohort.
Ibalizumab: It is a CD4-directed post-attachment inhibitor that blocks HIV entry and fusion into CD4 cells. While it does not prevent gp120 from binding CD4, it induces conformational changes that stop the gp120-CD4 complex from interacting with CCR5 or CXCR4, thereby preventing viral entry while maintaining normal immune function. It is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 and is used alongside the patient’s existing ART regimen.
Use of HIV, Attachment Inhibitors
HIV-1 attachment inhibitors reduce the viral replication by attaching directly to glycoprotein 120 (gp120) subunit on surface of the virus.
Fostemsavir: It is a prodrug of temsavir and a first-in-class HIV-1 attachment inhibitor. It binds to viral gp120 subunit and prevents the HIV from attachment to CD4+ T cells and other immune cells. It is indicated for use with other antiretrovirals in heavily treatment-experienced adults with multidrug-resistant HIV-1 who are failing their current ART due to resistance, intolerance, or safety concerns.
Use of Capsid Inhibitors
Capsid inhibitor binds directly to HIV-1 capsid protein (p24) hexamers, disrupting multiple stages of the viral lifecycle, including nuclear import of proviral DNA, virus assembly and release, and proper capsid core formation. Its approval was supported by the Phase 2/3 CAPELLA trial, in which 81–83% of participants with multidrug-resistant HIV-1 achieved viral loads below 50 copies/mL at week 26 when lenacapavir was combined with an optimized background regimen.
Lenacapavir: It is a first-in-class capsid inhibitor administered twice yearly. It is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection and is also approved for PrEP in adolescents and adults weighing at least 35 kg (77 pounds).
Use of Complete Regimen Combinations
Fixed-dose combination regimens simplify HIV treatment by reducing the number of pills and dosing frequency, thereby improving patient adherence. Two-, three-, and four-drug combinations are available to achieve this.
Cabotegravir/rilpivirine: Monthly injectable regimen for adults with HIV-1 who are virologically suppressed, replacing a stable ART regimen. Initiated after a 30-day oral lead-in with the same drugs to ensure safety and tolerance.
Dolutegravir/rilpivirine: Dolutegravir and rilpivirine form the first 2-drug, fixed-dose regimen approved for HIV-1, indicated for adults who are virologically suppressed on a stable ART regimen for at least 6 months with no history of treatment failure or known resistance.
Dolutegravir/lamivudine: Dolutegravir/lamivudine is a first 2-drug, fixed-dose regimen for treatment-naïve adults and adolescents (≥12 years, ≥25 kg) with HIV-1, combining an integrase inhibitor and an NRTI, for patients without known resistance to either drug.
Elvitegravir/cobicistat/emtricitabine/tenofovir AF: Genvoya is a once-daily antiretroviral combination tablet for treatment-naïve adults and adolescents (≥12 years) or as a replacement regimen in virologically suppressed patients. It contains elvitegravir (INSTI), emtricitabine and tenofovir AF (NRTIs) and cobicistat as a pharmacokinetic booster.
Darunavir/cobicistat/emtricitabine/tenofovir AF: Darunavir/cobicistat/emtricitabine/tenofovir AF is a once-daily, complete antiretroviral regimen for adults and adolescents (≥40 kg) with HIV-1 infection, suitable for treatment-naïve patients or those virologically suppressed on a stable ART regimen, with no known resistance to darunavir or tenofovir.
Emtricitabine/rilpivirine/tenofovir AF: Emtricitabine/rilpivirine/tenofovir AF is a once-daily, complete antiretroviral regimen for treatment-naïve adults and adolescents (≥12 years) or for virologically suppressed patients on a stable ART regimen, containing one NNRTI (rilpivirine) and two NRTIs (emtricitabine and tenofovir AF).
Elvitegravir/cobicistat/emtricitabine/tenofovir DF: Elvitegravir/cobicistat/emtricitabine/tenofovir DF is a once-daily, complete antiretroviral regimen for treatment-naïve adults, combining an integrase inhibitor (elvitegravir), two NRTIs (emtricitabine and tenofovir DF), and cobicistat, a CYP3A4 booster that enhances elvitegravir’s bioavailability and prolongs its half-life.
Emtricitabine/rilpivirine/tenofovir DF: Emtricitabine/rilpivirine/tenofovir DF is a complete once-daily regimen containing two NRTIs and one NNRTI, indicated for treatment-naïve HIV-1 patients aged ≥12 years with HIV-1 RNA ≤100,000 copies/mL, or for virologically suppressed patients on a stable ART regimen to replace their current therapy.
Bictegravir/emtricitabine/tenofovir AF: It is a three-drug complete regimen combining an integrase inhibitor (bictegravir) with two NRTIs (emtricitabine and tenofovir alafenamide). It is indicated to treat HIV-1 in ART-naïve adults and pediatric patients ≥25 kg or to replace a stable regimen in virologically suppressed patients without resistance to any component.
Efavirenz/lamivudine/tenofovir DF: It is a three-drug regimen in combination of one NNRTI (efavirenz) with two NRTIs (lamivudine and tenofovir DF). It is indicated to treat HIV-1 infection in adults and children who have ≥35 to 40 kg weight.
Doravirine/lamivudine/tenofovir DF: It is a once-daily, three-drug regimen to treate HIV-1 infection. It is indicated for treatment-naĂŻve adults or as a replacement therapy in virologically suppressed patients on a stable ART regimen with no history of treatment failure or known drug resistance.
Use of Antiretroviral Combinations
Abacavir/dolutegravir/lamivudine: It is a fixed-dosage combination drug. It contains two NRTIs (abacavir 600 mg and lamivudine 300 mg) and an integrase strand transfer inhibitor (dolutegravir 50 mg). Dose adjustment of dolutegravir may be needed when used with strong CYP3A4 inducers, typically by adding a single evening dose of dolutegravir.
Emtricitabine/tenofovir DF/efavirenz: It is a NNRTI and NRTI combination product which is used to treat HIV infection.
Emtricitabine/tenofovir DF: A combination of two NRTIs used with other ART agents for treating HIV-1 infection in adults and children ≥17 kg who can swallow tablets. Also approved for pre-exposure prophylaxis (PrEP) in high-risk adults and adolescents, including MSM, serodiscordant couples, IV drug users and other populations at increased risk of the HIV-1 infection.
Emtricitabine/tenofovir AF: It is used with other ART agents to treat HIV-1 infection in adults and adolescents ≥12 years. It is approved for sexual pre-exposure prophylaxis (PrEP) in at-risk adults and adolescents excluding those at risk via receptive vaginal sex.
Lamivudine/tenofovir DF: It is indicated for the usage with other antiretroviral agents to treat HIV-1 infection in adults and children who have ≥35 kg weight.
Darunavir/cobicistat: It is used as part of antiretroviral therapy for HIV-1 infection in adults and children whose age is ≥6 years and weigh at least 25 kg.
Use of CYP3A4 Inhibitors
Ritonavir and cobicistat are used in ART regimens to inhibit CYP3A-mediated metabolism of antiretroviral drugs, increasing their systemic levels and enhancing antiviral efficacy.
Cobicistat: It is a CYP3A inhibitor which is used to boost the systemic exposure of specific antiretrovirals like atazanavir or darunavir when it is given once daily with other ART agents.
Use of Antibiotic, Sulfonamide Derivative
Antimicrobial therapy should be broad enough to target all pathogens that are likely to be present in the given clinical scenario.
Sulfamethoxazole and Trimethoprim: It blocks the synthesis of dihydrofolic acid and inhibits the bacterial growth.
Use of Growth hormone releasing factor
It reduces the visceral adipose tissue.
Tesamorelin: It is a growth hormone–releasing factor (GRF) analog, stimulates growth hormone and IGF-1 production, promoting anabolic and lipolytic effects, and is indicated for reducing excess abdominal fat in patients with HIV-associated lipodystrophy.
Both our subscription plans include Free CME/CPD AMA PRA Category 1 credits.
On course completion, you will receive a full-sized presentation quality digital certificate.
A dynamic medical simulation platform designed to train healthcare professionals and students to effectively run code situations through an immersive hands-on experience in a live, interactive 3D environment.
When you have your licenses, certificates and CMEs in one place, it's easier to track your career growth. You can easily share these with hospitals as well, using your medtigo app.
