Chapter 128: Human Immunodeficiency Virus Infection

Human immunodeficiency virus (HIV) is a retrovirus that infects and destroys helper T cells leaving untreated patients vulnerable to opportunistic infections and cancers. HIV-1 is the most common subtype and is distributed worldwide. HIV-2 is primarily found in West Africa.

One of the most amazing success stories of our lifetime is the transformation of HIV infection from a rapidly fatal disease to a chronic health condition. As a direct result of suppression of the HIV virus with antiretroviral therapy, transmission rates have also dropped. However, with one exception occurring in very exceptional circumstances (ie, bone marrow transplant), we have yet to cure anyone of HIV infection. As a result, a growing wave of people living, and aging, with HIV infection (Figure 128-1) are reaching middle and advanced age. As of 2010, 52% of those living with HIV infection in San Francisco and 42% of those in New York City were 50 years of age or older. As of 2011, 70% of HIV-infected individuals receiving care within the national US Veterans Administration Healthcare System were 50 years of age or older. Across the United States, the percentage of adults living with HIV infection who are 50 years of age or older grew from 17.4% in 2001 to 36.2% in 2010.

With increased prevalence, transmission rates are also likely to increase within this age group—especially among those who live in areas with relatively high geographic prevalence including Florida, New York, and Washington, DC. In addition to high local prevalence, ongoing risk behaviors and delayed diagnosis and treatment further enhance the risk of transmission. Those aging with HIV are more likely than other aging individuals to use various psychoactive substances including alcohol, marijuana, cocaine, and opioids which can both interfere with antiretroviral adherence and increase unsafe sexual encounters. Use of sildenafil (Viagra) and related medications to treat erectile dysfunction and enhance sexual performance may increase sexual risk behavior. Additionally, older men are less likely to use condoms and postmenopausal women may be less likely to request that they be used as they face no risk of pregnancy. Age-associated erectile changes may make condom use difficult, and age-associated declines in immunity may place older individuals at higher risk of transmission with each exposure. Finally, older individuals appear to present later in the course of HIV disease compared to younger individuals, extending the period of highest infectivity due to unsuppressed HIV-1 RNA.

Of note, research in age and aging with HIV is still in its infancy. To date, research has focused on comparing outcomes among persons aged 50 years and older to their younger counterparts and to age matched uninfected comparators. A threshold of 50 years of age for aging research is supported in HIV for both sociological and medical reasons: People aged 50 years and older with HIV often feel marginalized because of age and this group experiences a shortened survival and greater burden of comorbid disease. However, since most gerontological studies use a threshold of 65 years of age or even older thresholds, it will be important to study effects of HIV among those of more advanced age. In some cases interactions between HIV and comorbidities associated with aging may only become apparent at more advanced ages. This may be particularly true for neurocognitive disorders, cancer, lung disease, and cardiovascular disease.

Future research will need to differentiate people aging with HIV who have maintained suppressed HIV-1 RNA versus those with continued detectable virus. Susceptibility to HIV-associated non-AIDS conditions varies by level of viral suppression, and in some cases, by level of CD4 recovery after antiretroviral therapy (ART). We do not have a very clear idea of what happens among those in their seventh or eighth decade of life compared to similar aged uninfected individuals. Individuals who are diagnosed early in their disease process, achieve and maintain excellent HIV-1 RNA suppression, do not gain excess weight after ART initiation, and avoid ongoing substance use are likely to experience a very different aging trajectory from those who do not.

Importantly, the study of HIV infection among aging individuals may provide a template for improving the management of complex chronic disease more generally especially among special populations of aging individuals—people of color, sexual minorities, those with few socioeconomic resources, and those aging with heavy substance use histories. These groups are often ignored or understudied when more common conditions of aging are addressed.

Little is known about the presentation of acute HIV infection in older patients. In younger patients, acute infection may be completely asymptomatic or present as a flu-like syndrome. Like older HIV-uninfected individuals, older people with HIV infection underreport symptoms compared with younger individuals, and this underreporting may be especially pronounced in older black patients. In addition, the symptoms associated with HIV infection are also common among older patients without HIV infection.

Among those persons 50 years of age and older who are chronically infected with HIV and in care, the most common self-reported symptoms are fatigue, peripheral neuropathy, problems sleeping, muscle or joint pain (myalgias or arthralgias), problems with having sex, and cognitive difficulties. Prior to the start of antiretroviral therapy, people with HIV infection have lower body mass indices and lower cholesterol values than demographically matched controls. Common laboratory abnormalities include leucopenia, anemia (predominantly normocytic), transaminitis, and hyperproteinemia. Thus, unless the clinician has a high index of suspicion in the older patient, or routinely screens for HIV infection, it may be difficult to identify HIV-positive individuals. HIV-infected women enter menopause at a median age of 46 years compared to the median of 51 years among uninfected women. HIV-infected women also tend to experience more pronounced symptoms during menopause. Hypogonadism is also prevalent among men infected with HIV. Like the symptoms, signs, and laboratory abnormalities discussed above, most of the diagnoses made in older people with HIV are not unique to HIV infection.

Physicians and their older patients are both likely to underestimate the risk of HIV infection. The patient may be misinformed or in denial. The physician may mistakenly believe that the patient has not had unprotected sex with multiple partners or used injection drugs—even in the remote past. Every major medical facility caring for those with HIV infection can recount multiple stories of older patients undergoing extended and expensive work-ups over the course of several months or even years until someone sends a test for HIV infection. Nationally, the median CD4 cell count at presentation for HIV has improved but these improvements have lagged by 50 to 100 cells for those 50 years of age and older.

Screening

Because untreated individuals who are unaware of their HIV infection are more likely to infect others and because benefit from antiretroviral treatment is less among those presenting with advanced disease, timely detection and treatment of HIV infection among older infected individuals is a growing concern. The Centers for Disease Control and Prevention and the US Preventive Services Task Force (USPSTF) currently recommend that clinicians screen adolescents and adults aged 15 to 65 years and all pregnant women, including those who present in labor and whose HIV status is unknown. They also recommend that younger adolescents and older adults should be screened if they are known to be at increased risk. All of these recommendations are grade A recommendations (USPSTF).

The Centers for Disease Control and Prevention goes further to say that opt-out screening (screening after notifying the patient that an HIV test will be performed unless the patient declines) is now recommended in all health care settings. Specific signed consent for HIV testing is no longer required. General informed consent for medical care is considered sufficient to encompass informed consent for HIV testing.

Regardless of age, any patient reporting any of the following: multiple sexual partners and unprotected sex; a prior diagnosis of a sexually transmitted disease (gonorrhea, syphilis, chlamydia, or trichomonas); or illicit drug use is at high risk for HIV infection and should be tested. Note that in some cases, an individual in a monogamous relationship may present with a sexually transmitted disease because their partner has more than one partner. These individuals are at risk for HIV as well and should be tested. While, intravenous drug use is a risk factor in itself; illicit drug use, IV or otherwise, is associated with risky sexual behavior. Hazardous alcohol use is also an important risk factor for unprotected sex with multiple partners. Because older patients may not spontaneously report these behaviors and conditions, physicians should routinely ask (Table 128-1).

HIV Testing

HIV testing should be conducted as part of a diagnostic workup in any patient with unexplained anemia, pancytopenia, peripheral neuropathy, oral candidiasis, herpes zoster, recurrent bacterial pneumonia, anal cancer, or any of the more traditional AIDS-associated conditions (Pneumocystis carinii pneumonia, Kaposi sarcoma, atypical mycobacterium, tuberculosis, non-Hodgkin lymphoma). Finally, any patient for whom more common causes of debilitating fatigue or weight loss have been eliminated should be tested for HIV.

The blood test that has been used for more than a decade is simple, accurate (sensitivity and specificity > 99.9%), and widely available. It involves two steps. The first step is a screening enzyme immunosorbent assay for HIV antibody. If this test is positive, a western blot is used to confirm the diagnosis. If the first test is negative, the patient is considered uninfected. Even in low-risk populations such as blood donors, the false-positive rate of these combined tests is low (< 0.001%). This somewhat cumbersome test is being replaced at many sites with a dual antigen-antibody test with similar accuracy. If positive, a confirmatory antibody test (not the traditional Western blot) is performed. If that test is negative, a quantitative PCR is then performed to document acute HIV infection. Of note, the diagnosis of acute HIV infection requires antigen detection testing since antibody will not yet be detectable.

When an individual tests positive, it is important to inform them of these results with as much care as you would any other life-changing diagnoses like that of cancer or diabetes. It is particularly important that you facilitate their integration into a clinical practice with substantial experience in the treatment of HIV infection. Comanagement may be needed if the patient has a substantial burden of age-related comorbid conditions or frailty.

Of note, home tests that employ a mouth swab (OraQuick In-home HIV test) or pricking your finger (Home Access HIV-1 Test System), akin to home glucose monitoring, are now readily available. While the blood test requires sending the sample in for centralized lab analyses and calling in for results, the mouth swab test results are available within 20 minutes and completely anonymous. Of note, the accuracy of the mouth swab test is not as high as the other tests because the level of antibody in oral fluid is lower. This may result in delayed diagnosis. Up to 1 in 12 people who are infected may test negative with this test.

Life Expectancy/Staging/Prognosis

After acute infection, the natural history of HIV infection is usually one of progressive immunodeficiency reaching a symptomatic threshold within approximately 8 to 12 years after infection. If infection goes untreated, survival from the time of first AIDS-associated diagnosis is on the order of 1 to 2 years (median). Survival with current multiclass, combination antiretroviral therapy confers between 20 to 30 additional years of survival depending upon CD4 cell count and age at treatment initiation. Those who achieve HIV-1 RNA suppression before experiencing substantial CD4 cell count loss (ie, never experience a CD4 count below 500 cells/mL) appear to experience a near normal life expectancy so long as they maintain HIV-1 RNA suppression. Prognosis is poorer among those who present late for care, fail to adhere to their treatment regimen, and/or develop widely resistant virus.

Older individuals appear to adhere more effectively to antiretroviral therapy and are quite successful at achieving HIV-1 RNA suppression, but experience a slower improvement in CD4 cell count. They may also be more susceptible to short- or long-term adverse drug effects from antiretroviral therapy.

Age, CD4 cell count, level of HIV-1 RNA suppression after ART initiation, and routine markers of organ system injury including hemoglobin, creatinine, aspartate transaminase, alanine transaminase, platelet count, and hepatitis C status all confer additional information about prognosis. These clinical biomarkers have been organized into a widely validated prognostic index, The Veterans Aging Cohort Study (VACS) Index (http://medicine.yale.edu/intmed/vacs/welcome/vacsindexinfo.aspx see Table 128-1), which is predictive of all-cause mortality, HIV-specific and non-HIV causes of death, hospitalization, fragility fractures, functional performance, and neurocognitive performance. Changes in the VACS Index reflect response to antiretroviral therapy more completely than do isolated changes in CD4 cell count and HIV-1 RNA.

Selection and Initiation of Antiretroviral Treatment

Once patients are diagnosed with HIV infection, initiation of antiretroviral therapy becomes a pressing concern both for the personal benefit of the patient and to prevent any further transmission of the virus. Older individuals experience higher HIV-1 RNA viral loads and a more rapid decline in CD4 cell count prior to treatment and experience delayed diagnosis and treatment compared to younger patients.

All individuals infected with HIV experience dramatic and sustained benefit from lifelong antiretroviral therapy. Standard regimens require multiple medications from multiple medication classes. The most common regimens require at least three daily medications, either a nonnucleoside reverse transcriptase inhibitor or a protease inhibitor and two nucleoside reverse transcriptase inhibitors. New classes are recently available and others are under development. Many patients in the United States now take a single coformulated tablet once a day. These newer medications have reduced adverse effects and increased rates of successful viral suppression. They also appear to be more tolerate of minor variations in adherence. In many settings 80% to 90% of those newly initiating ART achieve suppression of the HIV-1 RNA to below 50 copies/mL. and most are able to sustain this level of suppression for many years. There is a growing consensus that treatment should begin immediately after diagnosis, regardless of CD4 cell count. This strategy is likely cost effective as it minimizes risk of HIV transmission, AIDS defining illnesses, and later emergence of HIV-associated non-AIDS conditions.

There are now many antiretrovirals from which to choose and this selection should be informed by consultation with an experienced HIV care provider in light of an HIV-1 RNA viral resistance profile and careful consideration of preexisting organ system injury, mental illness, or, in the case of abacavir, genetic susceptibility to toxicity. Patients require close follow-up for the first several months of therapy to ensure that HIV-1 RNA suppression is achieved and that no concerning adverse events occur. After the first 6 to 12 months of therapy, if viral suppression is achieved, the patient has a CD4 count well above 350 cells/mL, and there are no active issues, patients may be monitored less frequently. While selection of antiretroviral regimens should be informed by an experienced HIV provider, once patients have achieved HIV-1 RNA suppression, their care might be managed by a primary care provider or geriatrician with consultation as needed.

Weight gain after ART initiation is common, clinically significant, and occurs even among those already overweight or obese, likely due to the decreased metabolic demand that results from effective viral suppression. While some weight gain may be beneficial among those who are underweight or normal weight, because weight gain is associated with incident hypertension, hyperlipidemia, diabetes, and hepatic steatosis, those who are overweight or obese should be counselled to reduce caloric intake or increase exercising to avoid gaining weight after ART initiation.

Chronic Disease Management

Even for the patient achieving and maintaining HIV-1 RNA suppression, aging with HIV is not the same as aging without HIV infection. Chronic HIV infection is a complex disease in which it is often impossible to tell whether a new condition is the result of HIV, HIV treatment, or comorbidity (and/or treatment for the comorbidity). In many cases, the likely answer is that there is no single etiology but rather the conditions results from a combination of some or all of these factors.

No one is immune from HIV infection. Nevertheless, HIV infection occurs more commonly among the homeless, members of inner-city minority or sexual minority populations, or those suffering from psychiatric illness compared with the general population of people 50 years of age or older. General medical comorbidities such as hypertension, diabetes, hepatitis C, and obstructive lung disease are common in these populations. Depression and severe mental illnesses such as psychosis and posttraumatic stress disorder are also more common among older people with HIV infection than among the general population of people 50 years of age or older. Older people with HIV infection may have multiple reasons to have cognitive dysfunction, whether from cognitive diseases of aging (multi-infarct dementia or Alzheimer disease) or from HIV (minor cognitive motor disorder or HIV-associated dementia).

As noted above, people aging with HIV infection are at higher risk for a number of age associated chronic diseases also associated with HIV (HANA conditions). While they do not appear to experience any one of these conditions dramatically earlier than demographically similar uninfected individuals, they do appear to experience a greater overall burden of disease from multiple conditions as reflected in greater polypharmacy, higher levels of physiologic frailty as measured by the VACS Index, decreased functional performance, and more substantial neurocognitive issues.

As a group, patients infected with HIV who are aged 50 years or older are also more likely than uninfected demographic counterparts to have consumed hazardous amounts of alcohol, use illicit drugs (especially marijuana, cocaine, and opioids), and smoke cigarettes. These behaviors increase risk of liver, lung, and heart disease. They also increase risk for a number of common cancers and contribute to neurocognitive dysfunction.

Among patients who continue to drink hazardously and or to use illicit drugs, adherence to antiretroviral therapy and ongoing organ injury are likely to be important issues. Patients should be asked directly about alcohol, cigarette, and illicit drug use, and encouraged to stop or curtail ongoing use. Any patient reporting current drug or alcohol use should be questioned closely regarding treatment adherence and monitored for signs of organ system injury.

More than half of HIV-infected patients smoke. Smoking increases the risk of pulmonary disease, cancer, cardiovascular disease, and fragility fractures, and impairs immune response to ART. It clearly increases risk of mortality. Recent analyses suggest that smoking is associated with a greater number of lost life-years than that associated with treated HIV infection.

Thus, it is important to encourage patients to stop smoking. The average successful patient will attempt quitting several times before succeeding. There are many excellent programs available to assist patients in quitting including online help programs. The use of nicotine replacement therapies may facilitate quitting. Early data suggest greater quit rates with varenicline, but greater adverse events.

Surprisingly little is known about the chronic effects of marijuana among middle-age and older individuals but what is known among younger individuals suggests that chronic use is likely to impair antiretroviral adherence and cognitive functioning and may contribute to obesity. There are no established pharmacologic treatments for marijuana use, but cognitive behavioral therapy or brief motivational interviewing would likely be helpful.

Even moderate levels of alcohol consumption may be harmful among those aging with HIV infection. This is, in part, because HIV infection alters the absorption of alcohol resulting in higher blood levels of alcohol among those with untreated HIV infection compared with uninfected individuals for the same amount of alcohol consumed. It remains to be seen if this difference persists after successful ART. Of note, on-going alcohol use may also impair efforts to stop smoking, to maintain a healthy body weight, or to successfully treat depression. Cognitive behavioral therapy or brief motivational interviewing can be effective alone or in combination with pharmacotherapy for those who drink at higher levels.

HIV-Associated Non-AIDS Conditions

After ART initiation, the incidence of AIDS conditions as defined by the Centers for Disease Control and Prevention drops dramatically and conditions such as Kaposi sarcoma, if present at diagnosis, may resolve without additional treatment. However, the Strategies for Management of Antiretroviral Therapy (SMART) trial demonstrated that viral suppression through ART also decreases incident non AIDS conditions including liver disease, kidney disease, lung disease, and cardiovascular disease, there are conditions for which those with HIV infection appear at greater risk even after adjusting for all established risk factors. The list of these conditions continues to grow and includes cancers associated with viral infections (eg, Hodgkin lymphoma, anal cancer, liver cancer), lung cancer, cardiovascular disease, liver cirrhosis, chronic obstructive lung disease, and renal failure. A hallmark of these conditions is that they are more common among those with unsuppressed HIV-1 RNA and/or lower CD4 cell counts compared with HIV infected individuals with suppressed HIV-1 RNA or higher CD4 cell counts and most are less common after ART initiation.

While the evidence for the association of these conditions with HIV infection compared with demographically and behaviorally similar uninfected individuals continues to grow, the mechanistic explanation for this association is likely complex. Potential mechanisms include immune dysfunction, dysregulation, and suppression; chronic inflammatory stimulation due to reservoirs of HIV-1 RNA replication and to chronic microbial translocation; hypercoagulability; and direct effects of viral proteins. Thus the biomarkers most relevant to studying this phenomenon have yet to be established and likely depend, to some degree, upon the condition in question.

Polypharmacy

Once people with HIV initiate ART, typically in their third or fourth decade of life, polypharmacy (being on five or more chronic medications) becomes the norm a full decade before those without HIV experience this syndrome. Further, due to the sensitivity of many antiretrovirals to drug-drug interactions and substantial preexisting organ system injury among those with HIV, those with HIV infection may be particularly susceptible to the harms associated with polypharmacy. These harms include decreased medication adherence and increased serious adverse drug events including organ system injury, hospitalization, geriatric syndromes (falls, fractures, and cognitive decline), and all-cause mortality.

In addition to antiretroviral medication, common medication classes among HIV-infected individuals with polypharmacy include antihypertensives, diuretics, statins, antidepressants, antacids, and nonopioid analgesics. Many of these medications have well established drug-drug interactions with commonly prescribed antiretrovirals. Of note, HIV-infected individuals are also experiencing an increasing rate of chronic prescription opioid and benzodiazepine use as has been documented in the general population. Of equal concern are medications taken over the counter and dietary supplements, which are almost never accurately documented in the medical record and may be particularly problematic. Recent IDSA guidelines recommend review of the complete medication lists with thoughtful consideration and discussion with the patient to try to prioritize medications and simplify regimens whenever possible.

It will also be important to attempt to keep the number of total medications (for HIV and non-HIV conditions) down in order to avoid drug-drug interactions and cumulative toxicity and to screen regularly for evidence of liver, kidney, and bone marrow toxicity. Antiretroviral treatment timing and choice should be made balancing the individual’s cumulative organ system frailty and their likely risk of adverse events against the substantial benefit of early and aggressive HIV treatment.

Hepatitis C

A large proportion of those with HIV infection in the United States are also infected with hepatitis C. The recent availability of highly effective and less toxic treatment for hepatitis C raises additional issues. HIV-infected individuals with hepatitis C coinfection experience more rapid progression of liver cirrhosis and a heighted risk of hepatocellular cancer. Recent data have demonstrated that suppression of HIV-1 RNA with antiretroviral treatment slows progression of liver disease among those coinfected with hepatitis C. Unlike HIV infection, hepatitis C can be cured. Given the substantial risk for cirrhosis, liver failure, and hepatoma among these individuals, it would seem appropriate to consider treating coinfected individuals earlier rather than later in the course of their disease.

Finding a Balance

The challenge for the aging patient with HIV infection and their provider is to balance screening and treatment for high risk, modifiable conditions including cancer, hypertension, hyperlipidemia, hepatitis C, and substance use against harm from polypharmacy. Whether or not a particular primary care practice is appropriate for an individual with HIV depends upon the individual’s life expectancy, the frequency and impact of the condition, the degree to which outcomes associated with that condition can be modified by timely medical intervention, and the risk associated with the intervention. For example, colon cancer screening via colonoscopy has a slight risk of perforation at the time of screen and a substantial risk of discomfort for the patient. Patients need to live at least 5 to 7 years after their screening for the benefit of the screening in decreased risk of death from colon cancer to outweigh the risk of perforation and the pain and discomfort of the procedure. Conversely, more aggressive screening for anal cancer may be indicated because of the increased incidence of this condition among those with HIV infection. Thus, it would be unwise to apply all “age appropriate” primary care guidelines for those without HIV to those with HIV infection without careful consideration for the individual’s prognosis, preferences for care, and personal risk of these conditions.

Finally, multimorbidity is the norm among those aging with HIV infection (Figure 128-2). Because of the overlapping complications and comorbid medical and psychiatric disease experienced by most patients with HIV infection, comprehensive care requires a team approach. No one specialist or generalist can hope to stay on top of optimal care in all these domains. HIV specialists need to turn to generalists and geriatricians when determining the best way to manage overlapping comorbid medical disease and to psychologists, psychiatrists, and social workers when managing psychiatric diseases. The management of alcohol and drug abuse also requires the insights of generalists familiar with the medical complications of these behaviors and of psychiatrics, psychologists, and social workers familiar with methods of managing these behaviors. In turn, generalists and geriatricians will need careful guidance from HIV specialists in determining when to start antiretroviral treatment, choosing optimal drug combinations, and determining when to stop or change therapy. For those who must manage patients far from specialty services, frequent telephone conferencing with specialists in HIV and with those experienced in the management of comorbid conditions is recommended.

HIV can be transmitted from one human to another when blood, semen, preseminal fluid, rectal fluids, vaginal fluids, or breast milk come into contact with a mucous membranes or damaged tissue or are directly injected into the bloodstream. The most common causes of transmission are unprotected sexual contact (risky sex) and sharing used needles during injection drug use (“dirty” needles). Transmission can also occur during pregnancy, childbirth, breast feeding, accidental needle punctures (medical occupational exposures), blood or blood product transfusion. HIV is not spread by air, water, mosquitoes or ticks, saliva, tears, sweat, casual contact, drinking fountains, or toilet seats.

The single most effective means of preventing HIV transmission is early diagnosis and treatment of those infected with HIV. This is because HIV-1 RNA viral suppression through antiretroviral therapy dramatically alters the risk of transmission given an exposure. It is also because people who are aware of their HIV status are more likely to alter their risk behaviors by using condoms, decreasing sexual activity, etc. Other means of prevention include pre-exposure prophylaxis (PrEP) for individuals known to be at very high risk of transmission (eg, serodiscordant couples) and use of condoms.

Health care systems are seeing an increasing proportion of older HIV-infected individuals presenting for care. These trends reflect in part new seroconversion at more advanced age and, in part, late presentation for care. Based on CD4 count at presentation among European and North American cohorts, older individuals present at a later stage of disease progression than do their younger counterparts and later presentation is associated with poorer clinical response to ART. Older people with HIV infection are dramatically more likely to experience social isolation (Figure 128-3). Further, people aging with HIV are substantially more likely to be hospitalized, to experience MICU admission, and polypharmacy. Those with HIV are also more likely to have other chronic viral infections including hepatitis C, hepatitis B, CMV, and HPV. How these patients and their many transitions between inpatient and outpatient care, general medical care and specialty care, and skilled nursing facility care will best be managed in the future remains to be seen. What is nearly certain is that they will place new demands on parts of the health care system including short- and long-term nursing facilities that have previously not managed those with HIV infection in any substantial numbers.

Geriatricians should actively consider screening patients for HIV infection, especially if they live in areas of high local prevalence. Geriatricians will also be increasingly needed to comanage effects of aging and cumulative frailty; comorbid medical and psychiatric conditions; and polypharmacy. They will also need to advise administrators in skilled nursing facilities and nursing homes on how to appropriately care for these patients.