HIV Type 1

General Principles


HIV type 1 is a retrovirus that predominantly infects lymphocytes that bear the CD4 surface protein, as well as coreceptors belonging to the chemokine receptor family (CCR5 or CXCR4), and causes AIDS.


Diagnosis of AIDS by the Centers for Disease Control and Prevention (CDC) classification is made on the basis of CD4 cell count <200 cells/μL, CD4 percentage <14%, or development of one of the 25 AIDS-defining conditions.1


  • HIV type 1 is common throughout the world. By the most recent estimates, over 36 million people worldwide are living with HIV or AIDS, with a significant burden of disease in sub-Saharan Africa.2
  • In the United States, 1.1 million people are estimated to be infected with HIV with 15% of these people unaware of their infection. The CDC estimates there are nearly 40,000 new infections in the United States every year.
  • Despite comprising only 14% of the population in the United States, African Americans account for nearly 44% of all new cases of HIV in this country. Hispanics are also disproportionately affected by HIV. Women comprise approximately 19% of the US epidemic.3
  • MSM remain the population most heavily affected by HIV in the United States. Of all new HIV infections in 2009, 70% were MSM.4
  • HIV type 2 is endemic to regions in West Africa. It is characterized by much slower progression to AIDS and resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs).


  • After entering the host cell, viral RNA is reverse transcribed into DNA using the HIV reverse transcriptase. This viral DNA is inserted into the host genome through the activity of the viral integrase. The host cell machinery is then used to produce the relevant viral proteins, which are appropriately truncated by a viral protease. Infectious viral particles bud away to infect other CD4 lymphocytes.
  • Most infected cells are killed by the host CD8 T-cell response.
  • Long-lived latently infected cells persist, especially memory T cells.
  • Infection usually leads to CD4 T-cell depletion and impaired cell-mediated immunity over a period of 8–10 years.
  • Without treatment, >90% of infected patients will progress to AIDS, which is characterized by the development of opportunistic infections (OIs), wasting, and viral-associated malignancies.

Risk Factors

  • The virus is primarily transmitted sexually but also via parenteral and perinatal exposure.
  • The risk of transmission is low through blood transfusions (1 in 1.4 million). 
Sharing needles or needlestick injuries result in transmission in 50 per 10,000 exposures.
  • Among sexual practices, unprotected anal receptive intercourse carries the highest risk of transmission (138 per 10,000 exposures), followed by insertive anal intercourse, vaginal receptive intercourse, and vaginal insertive intercourse. Oral intercourse carries a low risk of transmission.


  • HIV transmission can be prevented by safe sex practices, which include condom use (male or female) for vaginal, oral, and anal intercourse, decreasing the number of sexual partners, and avoiding needle sharing.
  • Postexposure prophylaxis, or the provision of antiretroviral therapy (ART) after needlestick injury or high-risk sexual exposure, can prevent infection.
  • Pre-exposure prophylaxis (PrEP), or continuous ART in HIV-negative patients, has proven to decrease the rate of HIV transmission. The current guidelines recommend the use of PrEP for the following high-risk groups5
    • MSM
    • Heterosexual HIV-discordant couples
    • Those with multiple sexual partners with inconsistent condom use
    • Commercial sex workers
    • IV drug users
    • A combination of emtricitabine–tenofovir disoproxil fumarate (TDF/FTC) is the approved regimen for PrEP. Before starting PrEP, it is essential to document a negative HIV test, no signs or symptoms of acute HIV infection, hepatitis B status, and normal renal function. These patients should be followed every 3 months for repeat HIV testing as well as STI screening, risk reduction counseling, and every 6 months monitoring of renal function.


Clinical Presentation

  • Acute retroviral syndrome is experienced by up to 75% of patients and is similar to other acute viral illnesses such as infectious mononucleosis due to Epstein–Barr virus (EBV) or cytomegalovirus (CMV) infection. Common presenting symptoms of acute retroviral syndrome are fever, sore throat, nonspecific rash, myalgias, headache, and fatigue.
  • As the acute illness resolves spontaneously, many people present to care only after OIs (see later section for clinical presentations) occur late in infection once significant immune compromise has occurred (CD4 count <200 cells/μL). Late presentation can be avoided by routine screening.


Initial evaluation of persons with a confirmed HIV infection should include the following measures:

  • Complete history with emphasis on previous OIs, viral coinfections, and other complications.
  • Psychological and psychiatric history. Depression and substance use are common and should be identified and treated as necessary.
  • Family and social support assessment.
  • Assessment of knowledge and perceptions regarding HIV is also crucial to initiate ongoing education regarding the nature and ramifications of HIV infection.

Physical Examination

A complete physical examination is important to evaluate for manifestations of immune compromise. Initial findings may include the following:

  • Oral findings: thrush (oral candidiasis), hairy leukoplakia, aphthous ulcers
  • Lymphatic system: generalized lymphadenopathy
  • Skin: psoriasis, eosinophilic folliculitis, Kaposi sarcoma, molluscum contagiosum, Cryptococcus
  • Abdominal examination: evidence of hepatosplenomegaly
  • Genital examination: presence of ulcers, genital warts, vaginal discharge, and rectal discharge
  • Neurologic examination: presence of sensory deficits and cognitive testing

Diagnostic Criteria

  • The updated CDC guidelines for screening published in June of 2014 recommend the use of the fourth-generation assay, an antigen/antibody test that involves the detection of the p24 antigen as well as antibodies to HIV-1 and HIV-2. The p24 antigen is a viral capsid protein that can be detected as early as 4–10 days from acute infection, up to 2 weeks earlier than the antibody tests alone. An eclipse phase of infection, during which no testing is positive, still exists for up to 7 days after exposure.
  • If the fourth-generation assay is positive, then a differentiation test for HIV-1 and HIV-2 antibodies is performed as a reflex test.
  • If the HIV-1 and HIV-2 antibody differentiation test is negative for both HIV-1 and HIV-2, then nucleic acid testing (NAT) of HIV-1 RNA via PCR should be performed (Figure 16-1). If the NAT is positive, this indicates acute infection. Viral loads during acute infection are typically in the range of several million copies per milliliter, so a viral load <1000 copies/mL should be repeated to confirm infection.
Figure 16-1 Recommended laboratory HIV testing algorithm for serum or plasma specimens.
Descriptive text is not available for this image
From Centers for Disease Control and Prevention. Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations. Available at

Diagnostic Testing

The CDC recommends that all persons age 13–64 years be offered HIV testing in all health-care settings using an opt-out format.6

  • Persons at high risk should be screened for HIV infection at least annually. High-risk groups include: IV drug users, MSM, sexual partners of a known HIV patient, persons involved in sex trading and their sexual partners, persons with STIs, persons who have multiple sexual partners or who engage in unprotected intercourse, persons who consider themselves at risk, and persons with findings that are suggestive of HIV infection. More frequent screening (every 3–6 months) is sometimes indicated.
  • Other groups for whom HIV testing is indicated are:
    • Pregnant women (opt-out screening)
    • Patients with active TB
    • Donors of blood, semen, and organs
    • Persons with occupational exposures (e.g., needlesticks) and source patients of the exposures


  • Complete blood cell count and comprehensive metabolic panel with assessment of liver and kidney parameters, as well as urinalysis to evaluate for proteinuria and glycosuria.
  • CD4 cell count (normal range, 600–1500 cells/μL) and CD4 percentage. Significant immune deficiency requiring prophylactic antibiotics occurs with CD4 <200 cells/μL.
  • Virologic markers: Plasma HIV RNA predicts the rate of disease progression.
  • Fasting lipid panel. HIV is associated with an increased risk of metabolic syndrome and cardiovascular disease. Lipids can be affected by several antiretrovirals.
  • TB testing by interferon-γ release assay.
  • RPR test for syphilis screening, confirmed by fluorescent treponemal antibody assay.
  • Toxoplasma and hepatitis A, B (HBsAg, HBsAb, HBcAb), and C serologies.
  • Chlamydia/gonococcal urine/cervical probe for all patients. If patients report receptive anal sex, rectal probes for gonorrhea andChlamydia are recommended. For those reporting receptive oral sex, pharyngeal sample for gonorrhea should be obtained.7 NAAT is preferred.
  • Cervical Papanicolaou smear (most commonly using the thin prep method).
  • HIV drug resistance testing for reverse transcriptase and protease genes at baseline and with treatment failure. Integrase gene resistance testing should be performed for those failing integrase inhibitor–based regimens.
  • HLA B5701 for patients in whom one is considering the use of abacavir.
  • CCR5 tropism testing for patients in whom one is considering the use of maraviroc.
  • Glucose-6-phosphate dehydrogenase (G6PD) level on initiation of care or before starting therapy with an oxidant drug in those with a predisposing ethnic background.



  • From “Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: 2013 Update by the HIV Medicine Association of the Infectious Diseases Society of America”.8
  • Antibody response to vaccines is improved with undetectable HIV viral load and higher CD4 count.
  • Pneumococcal vaccine: HIV infection is an indication for both the pneumococcal conjugate (Prevnar) and polysaccharide (Pneumovax) vaccines. If naïve, the conjugate vaccine should be given initially, then the polysaccharide vaccine after at least 8 weeks. Some experts recommend deferring the vaccine until the CD4 cell counts are ≥200 cells/μL because responses are poor when vaccination occurs with low CD4 cell counts. A single booster Pneumovax after 5 years is recommended. If vaccinated with Pneumovax first, then should wait at least 1 year before administering Prevnar.
  • Hepatitis A virus (HAV): Vaccination for HAV is recommended if seronegative and MSM or have other indications (injection drug use, traveler to endemic country, chronic liver disease, coinfection with Hepatitis B or C.
  • Hepatitis B virus (HBV): Vaccination for HBV is recommended if seronegative.
  • Influenza: Annual inactivated influenza vaccination is recommended for all HIV-infected patients regardless of CD4 cell count. Use of the intranasally administered, live, attenuated vaccine is not currently recommended for HIV-infected persons.
  • Varicella: The live, attenuated varicella vaccine (chickenpox, Varivax) can be safely given to persons with CD4 cell counts ≥200 cells/mL but is contraindicated for persons with CD4 counts <200 cells/mL. There is currently no recommendation to give the zoster vaccine (Zostavax), although it may be considered in HIV-infected adults with CD4 counts ≥200 cells/mL.
  • Measles/mumps/rubella (MMR): MMR is a vaccine that can be safely given to persons with CD4 cell counts ≥200 cells/μL but is contraindicated for persons with CD4 counts <200 cells/μL.
  • Tetanus/diphtheria/pertussis: All adults should receive tetanus/diphtheria booster every 10 years with a one-time substitution with tetanus/diphtheria/acellular pertussis vaccine.
  • Human papillomavirus (HPV) vaccine: HPV-associated malignancies are common in HIV-infected patients. The three-dose vaccine series is safe and effective in HIV-positive subjects and is currently recommended for females aged 9–26 years, males aged 9–21 years, and MSM up to age of 26.



  • Current recommendations from the International AIDS Society-USA9 for the initiation of ART are to treat everyone infected with HIV, regardless of CD4 count.
  • In the case of patients with TB or cryptococcal meningitis, ART initiation may be slightly delayed to reduce the risk of serious immune reconstitution inflammatory syndrome (IRIS).
  • Treatment decisions should be individualized by patient readiness, drug interactions, adherence issues, drug toxicities, comorbidities, and the level of risk indicated by CD4 T-cell counts.
  • Women, especially if pregnant, should receive optimal ART to reduce the risk of vertical transmission.
  • Maximal and durable suppression of HIV replication is the goal of therapy once it is initiated. ART should be individualized and closely monitored by measuring plasma HIV viral load. Reductions in plasma viremia correlate with increased CD4 cell counts and prolonged AIDS-free survival. Isolated viral “blips” (<200 copies/mL) are not indicative of virologic failure, but confirmed virologic rebound should trigger an evaluation of adherence, drug interactions, and viral resistance.
  • Any change in ART increases future therapeutic constraints and potential drug resistance.
  • Antiretroviral drugs: Approved antiretroviral drugs are grouped into five categories. Experts currently recommend using three active drugs from at least two different classes to maximally and durably suppress HIV viremia.
    • Nucleotide and nucleoside reverse transcriptase inhibitors (NRTIs) constrain HIV replication by incorporating into the elongating strand of DNA, causing chain termination. All nucleoside analogs have been associated with lactic acidosis, presumably related to mitochondrial toxicity, although current recommended NRTIs have low incidence.
    • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit HIV by binding noncompetitively to the reverse transcriptase. Side effects of NNRTIs include rash, hepatotoxicity, and Stevens–Johnson syndrome (more likely with nevirapine). Central nervous system (CNS) side effects are commonly experienced with the use of efavirenz.
    • Integrase strand transfer inhibitors (INSTIs) target DNA strand transfer and integration into a human genome. They tend to have better safety and tolerability profiles than other classes and are associated with a rapid decrease in viral load after initiation. However, in mid-2018, the US Food and Drug Administration and the World Health Organization announced that cases of neural tube defects have been reported in babies of women with HIV who were on treatment with dolutegravir at the time of conception. The information comes from an interim analysis of an observational study of ART in Botswana. At the time of this writing, the CDC recommends that alternative regimens be considered in women of childbearing age and women be appropriately counseled. Raltegravir is the only other INSTI for which there are data on pregnant women, and higher rates of birth defects were not seen. Elvitegravir requires coadministration of the pharmacologic booster, cobicistat, which leads to increased incidence of gastrointestinal (GI) intolerance. Because of its interaction with the cytochrome P450 system, cobicistat has important drug interactions that should be evaluated. Few drug interactions exist with the other INSTIs: raltegravir, dolutegravir, and bictegravir.
    • Protease inhibitors (PIs) block the action of the viral protease required for protein processing late in the viral cycle. GI intolerance is one of the most commonly encountered adverse effects. These agents have also been associated with metabolic abnormalities such as glucose intolerance, increased cholesterol and triglycerides, and body fat redistribution. Boosting with ritonavir or cobicistat is a common practice to achieve better therapeutic concentrations. Owing to its metabolism via cytochrome P450, boosted PIs have important drug interactions, and concomitant medications should be reviewed carefully.
    • HIV entry inhibitors target different stages of the HIV entry process. Two drugs are available in this class. Enfuvirtide (T-20) is a fusion inhibitor that prevents the fusion of the virus into the host cell. T-20 is only available for use as an SC injection, 90 mg bid. The most frequent side effect for T-20 is a significant local site reaction after the injection. Maraviroc is a CCR5 receptor blocker. Initiation of CCR5 inhibitor requires baseline determination of HIV coreceptor tropism (CCR5 or CXCR4).
  • Initial therapy: ART should be started in an outpatient setting by a physician with expertise in the management of HIV infection. Adherence is the key factor for success. Treatment should be individualized and adapted to the patient’s lifestyle and comorbidities. Any treatment decision influences future therapeutic options because of the possibility of drug cross-resistance. Potent initial ART generally consists of a combination of two NRTIs, plus usually an NNRTI, an INSTI, or a boosted PI. INSTI-based regimens are optimal for initial therapy and are preferred. It should be noted that many of the first-line regimens are coformulated as single-tablet daily regimens. Tenofovir alafenamide (TAF) is a new formulation of TDF that is less likely to cause renal toxicity or bone mineral density issues but may have more drug interactions.
  • Treatment monitoring: After starting or changing ART, the viral load should be checked at 4–6 weeks with an expected 10-fold reduction (1.0 log10) and suppression to <50 copies/mL by 24 weeks of therapy. The regimen should then be reassessed if response to treatment is inadequate. When the HIV RNA becomes undetectable and the patient is on a stable regimen, monitoring can be done every 3–6 months.
  • Treatment failure is defined as less than a log (10-fold) reduction of the viral load 4–6 weeks after starting a new antiretroviral regimen, failure to reach an undetectable viral load after 6 months of treatment, detection of the virus after initial complete suppression of viral load (which suggests development of resistance), or persistent decline of CD4 cell count or clinical deterioration. Confirmed treatment failure should prompt changes in ART based on results of genotype testing. In this situation, at least two of the drugs should be substituted with other drugs that have no expected cross-resistance. HIV resistance testing at this stage may help determine a salvage regimen in patients with prior ART. The importance of adherence should be stressed. Referral to an HIV specialist is highly recommended in this situation.
  • Drug interactions: Antiretroviral medications, especially PIs, have multiple drug interactions. PIs and cobicistat both inhibit and induce the P450 system, and thus interactions are frequent with other inhibitors of the P450 system, including macrolides (erythromycin, clarithromycin) and antifungals (ketoconazole, itraconazole), as well as other inducers such as rifamycins (rifampin, rifabutin) and anticonvulsants (phenobarbital, phenytoin, carbamazepine). Drugs with narrow therapeutic indices that should be avoided or used with extreme caution include antihistamines (although loratadine is safe), antiarrhythmics (flecainide, encainide, quinidine), long-acting opiates (fentanyl, meperidine), long-acting benzodiazepines (midazolam, triazolam), warfarin, 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors (pitavastatin is the safest), and oral contraceptives. Sildenafil concentrations are increased, whereas methadone and theophylline concentrations are decreased with concomitant administration of certain PIs and NNRTIs.


Complications of ART: The long-term use of antiretrovirals has been associated with toxicity, the pathogenesis of which is only partially understood at this time.

  • Hyperlipidemia, especially hypertriglyceridemia, is associated mainly with PIs (especially ritonavir). Improvement has been seen after treatment with atorvastatin, pravastatin, pitavastatin, and/or gemfibrozil.
  • Peripheral insulin resistance, impaired glucose tolerance, and hyperglycemia have been associated with the use of PI-based regimens, mainly indinavir and ritonavir. Lifestyle changes or changing ART can be considered in these cases.
  • Osteopenia and osteoporosis are well described in HIV-infected individuals. The pathogenic mechanism of this problem is likely related to the inflammatory milieu of HIV itself, although the use of TDF may contribute. TAF is recommended over TDF in at-risk patients.
  • Osteonecrosis, particularly of the hip, has been increasingly associated with HIV disease.
  • Lipodystrophy syndrome is an alteration in body fat distribution and can be stigmatizing to individuals. Changes consist of the accumulation of visceral fat in the abdomen, neck (buffalo hump), and pelvic areas, and/or the depletion of SC fat, causing facial or peripheral wasting. Lipodystrophy has been associated in particular with older PIs and NRTIs and is uncommon with currently recommended regimens.
  • Lactic acidosis with liver steatosis is a rare but sometimes fatal complication associated with NRTIs. The mechanism appears to be part of mitochondrial toxicity. Higher rates of lactic acidosis have been reported with the use of the older drugs stavudine and didanosine.

Special Populations


  • Maximally suppressive ART during pregnancy is critical in preventing mother-to-child transmission.
  • Current guidelines10 recommend that all HIV-infected partners in a couple planning pregnancy should attain virologic suppression before attempting conception.
  • Periconception PrEP for the HIV-uninfected partner may provide additional protection to reduce the risk of sexual transmission and should be discussed with the couple.
  • If a pregnant woman is already suppressed on ART and is tolerating that regimen, she should be maintained on her current ART regardless of the agents (including efavirenz). However, consideration should be given to avoiding dolutegravir in pregnancy until more data are available. Boosted darunavir should also be avoided because of low drug levels in pregnancy.
  • ART-naïve pregnant women should be started on a combination regimen of TDF/FTC with boosted Atazanavir daily, boosted Darunavir twice daily, or Raltegravir twice daily (especially if early in pregnancy). An alternative is Complera (combined rilpivirine, TDF, FTC) if started early in pregnancy and viral load <100,000 copies/mL.
  • Intrapartum IV zidovudine should be given to women during labor, although it is not required for women with consistent undetectable viral loads in late pregnancy.
  • Cesarean delivery should be scheduled for women with HIV viral loads >1000 in late pregnancy.
  • ART should be continued after delivery, consistent with current guidelines to treat everyone to prevent disease progression and HIV transmission.
  • Neonatal zidovudine prophylaxis should be given for 4 weeks if the mother has maintained virologic suppression. Neonatal prophylaxis using zidovudine and nevirapine with or without lamivudine should be offered if the mother did not receive antepartum suppressive ART.

Acute HIV Infection

ART given immediately after diagnosing acute infection may provide additional benefits.

  • The initiation of early ART in acute infection will suppress the extraordinarily high viral loads seen at this time and reduce further transmission of HIV.
  • Early ART may reduce the reservoir of latent virus.
  • Early ART maintains immune function and may allow for immunologic control of HIV off ART in resource-limited settings.


  • High rates of coinfection with HBV and hepatitis C virus (HCV) occur in HIV-infected patients.
  • Several HIV ART medications (tenofovir, emtricitabine, and lamivudine) also have activity against HBV. Any plan to treat HBV in coinfected patients should ensure that the regimen is fully active against both HIV and HBV. Discontinuation of ART that has been suppressing unrecognized HBV disease can result in reactivation of HBV with resultant acute, and sometimes fatal, HBV infection.
  • HCV therapy is rapidly evolving, and a complete delineation of treatment is available in Chapter 19, Liver Diseases.
  • Newer directly acting HCV agents appear to be as effective in HIV-infected patients as in monoinfected HCV patients; however, there are significant drug–drug interactions that should be considered, particularly with PI-based therapy, efavirenz, and therapy using the boosting agent cobicistat.


  • With the success of ART, HIV-related mortality is decreasing and HIV-infected persons are experiencing prolonged survival approaching the national survival average.
  • In 2015, the CDC estimated that 45% of HIV-infected persons were over the age of 50.
  • HIV infection is associated with premature end-organ disease, and thus many of the comorbidities associated with aging may be exacerbated in this growing population, including cardiovascular disease, insulin resistance and diabetes, osteoporosis, neurocognitive impairment, and physical frailty.
  • Certain non–AIDS-defining cancers are more common in HIV-infected patients, including anal cancer, lung cancer, and hepatocellular carcinoma. The extent to which this is due to HIV infection versus other risk factors such as smoking, HPV, and HBV/HCV coinfection is unclear.
  • The role of long-term HIV infection and ART use in these comorbidities is poorly understood, although the use of NNRTI and PI drug classes is associated with lipid profiles that may exacerbate cardiovascular disease.11 Higher rates of smoking and alcohol use also exacerbate these comorbidities.


  • All HIV-positive patients should be referred to a HIV specialist, if possible.
  • Counseling regarding contraception, safer sex practices, medication adherence, and proper health maintenance is essential.
  • Social work referral is important to ensure adequate social support system including housing, mental health assistance, and substance abuse treatment.


  1. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992;41(RR-17):1-19.
  2. World Health Organization. HIV/AIDS: Data and Statistics. Published 2018.
  3. Centers for Disease Control and Prevention.
  5. Centers for Disease Control and Prevention: US Public Health Service: Preexposure prophylaxis for the prevention of HIV infection in the United States—2017 Update: a clinical practice guideline. Published March 2018.
  6. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006;55(RR-14):1-17.  [PMID:16988643]
  7. Aberg JA, Kaplan JE, Libman H, et al. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV medicine association of the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(5):651-681.  [PMID:19640227]
  8. Aberg JA, Gallant JE, Ghanem KG, et al. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58(1):e1-e34.  [PMID:24235263]
  9. International Antiviral Society-USA. Guidelines. Published 2018.
  10. U.S. Department of Health and Human Services. Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. Published October 2018.
  11. Friis-møller N, Weber R, Reiss P, et al. Cardiovascular disease risk factors in HIV patients–association with antiretroviral therapy. Results from the DAD study. AIDS. 2003;17(8):1179-1193.  [PMID:12819520]


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