Hematologic Manifestations of HIV/AIDS

Introduction to Human Immunodeficiency Virus

An estimated 38 million people are living with HIV worldwide, of which approximately 25.4 million are on ART. Most cases currently come from sub-Saharan Africa, followed by the Caribbean. In 2019, there were 1.7 million new infections documented and 690,000 AIDS-related deaths recorded, with 23% attributed to men who have sex with men (MSM), 19% to clients of sex workers and their partners, 8% to sex workers themselves, 10% to drug use, 2% to transgender individuals, and the remaining 38% were unknown in the report (other factors include sexual assault of women and vertical transmission). Compared to 2010, 2019 witnessed a 23% reduction in the incidence of HIV and a 39% reduction in AIDS-related mortality. Furthermore, when looking at patients from 2015 to 2019, 59% of patients had an undetectable viral load. Despite substantial global strides in achieving control of HIV, there are fears expressed by the Joint United Nations Programme on HIV/AIDS (UNAIDS) driven by adverse consequences of COVID-19 on HIV, as a result of which 20% of individuals were unable to access therapy for longer than 6 months. As a result, UNAIDS projects an increase of 110,000 AIDS-related deaths in the upcoming 2 years.

In the United States, the incidence of HIV between 2014 and 2018 was 36,400 per year diagnosed with HIV due to any cause. Of the newly diagnosed cases, 66% were attributed to MSM, 24% to heterosexual contact, 7% to drug use, and 4% to a combination of MSM and drug use. When stratified by race/ethnicity, new HIV infections were found in 43% Black/African American, 26% Hispanic/Latino, 26% White, and 6% Other. This highlights a racial/ethnic disparity in healthcare, as Blacks/African Americans account for only 13% of the general population. Furthermore, there were evident disparities in geographical locations within the United States, where 52% of all the cases were in the South, 15% in the Northeast, 13% in the Midwest, and 20% in the West of the United States. The geographical disparity of cases in the US may be related to poverty, lack of access to health care, lack of appropriate sex education, or other (unknown) factors. These are all issues that pertain to the application of management strategies in the future.

AIDS is caused by two lentiviruses, HIV types 1 and 2 (HIV-1 and HIV-2) were first documented in the United States in 1981 when clusters of Kaposi sarcoma and pneumocystis jiroveci pneumonia in homosexual men were identified. HIV-1, a single-stranded RNA retrovirus with multiple names, was identified as the culprit. It is believed to have been zoonotically transmitted to humans from African primates of chimpanzee origin in central Africa, harboring simian immunodeficiency virus (SIV) (40% to 60% DNA homology to HIV-1). Although there are no confirmed direct cases of such transmissions, HIV’s cross-over to humans is attributed to the exposure of blood from hunting bushmeat, similar to other zoonoses (i.e., Ebolavirus and SARS-CoV-2). HIV-1 consists of four distinct lineages, termed groups M, N, O, and P, each of which resulted from independent cross-species transmission events. The majority of HIV infections are caused by the M group, which is further subdivided into 11 clades: A to K. Subtype B is the predominant type in the Western world, whereas subtype C is dominant in southern Africa. The lesser-known virus, HIV-2, also from the same family and often not accounted for when speaking about “HIV,” is mostly found in West Africa and is theorized to have been zoonotically transmitted from sooty mangabey monkeys. It has six phylogenetic lineages, A to F. HIV-2 is characterized by low virulence, lower viral loads (in the thousands rather than millions), and individuals that remain as “long term non-progressors” to AIDS. When individuals do progress, the process mimics HIV-1 in pathology. One needs to be aware of HIV-2, especially when immunodeficiency is suspected in an individual from West Africa, as the fourth generation immunoassay for HIV detection in the United States only tests for HIV-1; the earlier tests identified both.

As mentioned above, most HIV is transmitted sexually. In the US, it is mostly found in MSM, whereas in sub-Saharan Africa, it is transmitted mostly via heterosexual penile-vaginal sex. Exposure to infected blood via injected drug use is another common way to acquire HIV. In the past, hemophiliacs and thalassemics also acquired HIV through contaminated blood transfusions in the 1970s and 1980s before the virus was identified, and other transfused individuals receiving multiple single donor products also were infected. Currently, screening of donors and viral eradication in plasma products has made this mode of viral acquisition very rare to essentially non-existent. Mothers can also transmit HIV either perinatally (maternal-fetal hemorrhage of blood or swallowed blood during delivery) or to neonates via breastmilk. Individuals are at an increased risk of contracting HIV if the exposure involves a high viral load (in the acute phase of the infection) or having damage to the mucosa thus providing access to the virus; this can be seen in co-infections with other sexually transmitted infections (STIs) or in unprotected receptive anal sex. Factors that are protective against acquiring HIV include the use of protection during intercourse and male circumcision since foreskin harbors a concentration of Langerhans cells and T cells that are HIV targets. Protective factors preventing the host from transmitting HIV include achieving an undetectable viral load by the host through compliance with ART. This includes the use of ART during pregnancy and delivery to prevent vertical transmission to the neonate, reducing risk from 25.5% to 8.3% in the first study, with further reductions seen in subsequent studies. Sexual partners of HIV-positive patients can also reduce their risk by taking pre-exposure prophylaxis (PrEP) consisting of tenofovir disoproxil with emtricitabine or lamivudine. If an individual is exposed to a high-risk sexual encounter or a needle-stick injury, that is, healthcare workers, then post-exposure prophylaxis (PEP) of 28 days duration with tenofovir + emtricitabine with raltegravir is indicated. The efficacy of PEP has been observed in retrospective studies, where a Cochrane systematic review concluded that HIV-positive individuals were less likely to have been taking PEP (OR 0.19, 95% CI 0.06 to 0.52).

HIV is composed of a viral capsule constructed of glycoproteins gp120 and gp41 that form a lipid bilayer. These glycoproteins facilitate entry into cells by binding to the CD4 receptor and chemokine co-receptors CXCR4 and/or CCR5. Within the viral capsule, there are two positive-sense, single-stranded RNA strands that carry nine genes. Of those, three are integral to viral replication and survival: gag, pol, and env genes transcribe core proteins p24 and p17, reverse transcriptase and integrase, and the glycoproteins respectively. In the cytoplasm, the enzyme reverse transcriptase generates a single strand of DNA from which a double DNA strand (dsDNA) is transcribed. dsDNA enters the nucleus, and viral integrase integrates the viral DNA into the host cell’s DNA. From then on, the virus uses the host’s machinery to replicate. The viral protease enzyme is vital in the final step of cleaving gag and gag-pol precursor proteins into the functional units known as gp120 and gp41.

HIV not only infects T cells and myeloid cells (monocyte/macrophages) but also glial cells in the central nervous system (CNS). Furthermore, there are resting memory CD4 T cells that contain HIV but do not contribute to viral replication, making up a “latent HIV reservoir” posing important challenges to the eradication of the virus despite the ability to achieve an undetectable viral load with ART. This latter can be very important in that CNS virus and/or HIV in other extra-vascular locations may not be eradicated by highly active antiretroviral therapy (HAART) and contributes to viral resurgence and ongoing inflammation. Targeting viral entry as a therapeutic strategy gained traction when a CCR5-delta 32 mutation, found in populations of European descent, conferred resistance to acquiring HIV infection in homozygotes by inhibiting viral entry. Entry inhibitors have been developed to target the CCR5. Further, this was proven in vivo in the only two cases cured of HIV after receiving hematopoietic stem cell transplantation selected for the CCr5-delta 32 mutation as part of the treatment for acute myeloid leukemia and Hodgkin lymphoma. In 2018, a physicist in China used CRISPR-Cas9 gene-editing technology to genetically engineer twin girls with knockout CCR5 to prevent them from contracting HIV from their father. In addition to the questionable clinical reasoning and the unethical nature of his actions, one could speculate that the twin girls may be at increased risk of autoimmune diseases, as CCr5-delta 32 mutation has been associated with MS and lupus nephritis. Nonetheless, these cases demonstrate the utility of targeting viral entry as a therapeutic modality although once an infection has occurred, the previously described latent cells may vitiate this strategy.

In the United States, the 4th generation enzyme immunoassay is the standard HIV screening test used to detect HIV in the acute setting, where it is able to detect HIV IgM, IgG antibodies, and p24 antigen 15 to 20 days after exposure in comparison to the first-generation enzyme immunoassay, which only detected IgG after 35 to 45 days. The gold standard confirmatory testing for HIV remains the western blot, which has a window of 45 to 60 days. The presence of neutralizing antibodies has raised the question of a possible vaccine, which to this day remains a very active but puzzlingly unsolved area of research. One of the first vaccines developed in 1998 targeted neutralizing antibodies against gp120. Despite achieving high titers in the serum, the vaccine did not work as the targeted region V3 was shielded within a trimeric structure rendering it inaccessible. Surprisingly, in vivo animal experiments demonstrated that neutralizing gp120 antibodies were able to prevent HIV infection in pig-tailed macaques receiving IgG from HIV-1 infected chimpanzees. Other explanations for the lack of neutralizing antibodies in humans include the mutation rate of the HIV reverse transcriptase, giving HIV the ability to escape the host’s immune system. Furthermore, there are many clades and subtypes of the virus, another factor making a universal vaccine even more challenging.

The highest viral load is seen in the acute infection phase, accompanied by a drop in the CD4 count. The viral load starts to decline after approximately 4 weeks because of the cytotoxic T-cell immune response. The CD4 count then starts to increase but does not completely recover to what it was prior to the infection, referred to as an immunological set point. This is followed by the asymptomatic phase, which can last for a decade. Without anti-HIV treatment, the virus continues to replicate, and the CD4 T cell count continues to decline until an AIDS-defining opportunistic infection (OI) or a malignancy causes death. AIDS, by definition, occurs either when the CD4 T cell count is below 200 or by having one of the AIDS-defining illnesses irrespective of the CD4 T cell count. This “natural history” of untreated HIV infection is mitigated by starting antiretroviral therapy, where the CD4 T cell count starts to climb up and the HIV plasma viral load declines, potentially to undetectable levels using commercial assays with sensitivity typically down to 50 HIV viral copies/mL, thus reducing morbidity and mortality drastically (see Fig. 152.2 ).

Currently, HIV is treated with ART targeting the replication process at various stages from entry to maturity. There are nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), integrase inhibitors (INSTI), and protease inhibitors (PI). Additional ART includes entry inhibitors that prevent the virus from entering the targeted cells. These include enfuvirtide (Fuzeon) and maraviroc (Selzentry). Most HIV-infected persons are on 2 NRTI and 1 INSTI. In the past, a person with HIV took 13 or more pills a day, which in addition to side effects, added challenges to medication compliance. Nowadays, patients with HIV take 1 to 4 pills/day depending on the presence of co-infections with hepatitis B or C and the genotypic profile of HIV. Newer medications also offer an improved side effect profile, particularly for cytopenic effects, and there are single pills formulated to contain all of the antiretroviral therapy ( Table 152.2 ). Very recently, long-acting ART was approved, involving a monthly injection.

Antiretroviral therapy protects against opportunistic infections by restoring the CD4 T cell count and suppressing viral replication. The increase in CD4 T cell counts when starting ART can, in a minority of patients (~20%), sometimes lead to a paradoxical effect known as the immune reconstitution inflammatory syndrome (IRIS), especially if the individual had a low CD4 count or a high viral load. IRIS is a strong immune response characterized by cytokine release leading to an array of clinical syndromes. IRIS can resemble an opportunistic infection when the target is an occult infection that has now become unmasked in the setting of increased immune surveillance, that is, TB leading to constitutional symptoms or untreated hepatitis B leading to liver failure; or an autoimmune phenomenon, where the recovery of the immune system aggravates a pre-existing autoimmune disease, that is, thyroiditis, similar to the use of checkpoint inhibition. Depending on the cause, its management can target treatment of the inciting infection, which sometimes necessitates interrupting ART until treatment is completed if concurrent treatment is not possible. IRIS can resolve on its own if it arose from a previously recently adequately treated opportunistic infection, where the immune system precipitously recognizes remnants of it. To this end, IRIS remains a diagnosis of exclusion, with the main diagnostic clue being its timing.

In assessing a patient, one should consider the following three factors: the absolute T-cell count (CD4 count), followed by whether they take antiretroviral therapy, and whether the peripheral blood viral load (VL) is undetectable. These three factors determine the risk of imminent mortality ( Figs. 152.1 and 152.2 ). The classic analogy is to think of a train traveling on railroad tracks approaching the edge of a cliff. The speed of the train is the viral load, the distance to the cliff is the absolute T-cell count, and the cliff represents AIDS, where an individual is now at risk of an opportunistic infection or dying from complications of HIV.

Currently, in well-managed care settings, the great majority of HIV-infected patients are taking effective antiretroviral therapy that often involves 1 pill a day covering three agents. Testing for resistance is possible if a compliant patient nonetheless develops a high viral load, and the relatively large number of agents usually makes it possible to identify an effective combination. Isolated cytopenias are infrequent and generally seen in settings without available anti-HIV treatment. As will be discussed, thromboembolic events and malignancies persist, albeit at a lower rate.