Table of Contents

• Introduction
• Epidemiology
• HIV Susceptibility
• Mortality and Morbidity
• Late Presentation to Care
• Adherence
• Efavirenz Pharmacogenetics
• Adverse Effects of HAART
• Prevalence of Chronic Diseases
• Chronic Kidney Disease
• HIV-Associated Nephropathy
• Screening Algorithm for HIV-Related Renal Diseases
• HIV/Hepatitis B Coinfection
• HIV/Hepatitis C Coinfection
• Conclusion
• References

Introduction

This is Ada Adimora, from the University of North Carolina School of Medicine's Division of Infectious Diseases. I'm pleased to be talking with you today about "African Americans and HIV: New Developments in Clinical Management."

I'll briefly discuss epidemiology followed by recent studies of mortality and other HIV outcomes, pharmacogenetics and adverse effects of antiretrovirals and comorbid conditions that complicate the management of black patients with HIV.

Epidemiology

Let's begin first with the epidemiology. Since the beginning of the epidemic, the racial/ethnic distribution of AIDS diagnoses has changed and the proportion of AIDS cases among non-Hispanic blacks and Hispanics has increased. Among people who received an AIDS diagnosis in 2005, about 49% were non-Hispanic blacks, 28% were non-Hispanic whites, 21% were Hispanic, 1% were Asian or Pacific Islanders and less than 1% were American Indian or Alaskan Natives.¹

Thus, blacks now account for a disproportionate share of AIDS cases. They comprise about 13% of the U.S. population,² yet from 1981 through 2005 they represented about 40% of the total number of AIDS cases reported to the CDC [U.S. Centers for Disease Control and Prevention].³

The racial distribution by gender is especially striking: From 1981 through 2005, 60% of the women and 59% of the children reported as having AIDS were black. In 2005, of the 10,944 women reported with AIDS, 6,978 were black. Of the 30,956 men, 13,260 were black.

All the above-mentioned data are the reported AIDS cases. That is, these are people who came to medical attention. Population-based seroprevalence studies give a clearer picture that includes both people who have already been diagnosed and those who may not yet have come to medical attention. There are few current population-based HIV seroprevalence studies of the general U.S. population, but the available evidence suggests that HIV seroprevalence is high among blacks, much higher than among whites.

Among the more than 13,000 young adults and adolescents in the national population-based study called Add Health [The National Longitudinal Study of Adolescent Health], the HIV seroprevalence among blacks was estimated to be almost 0.5%, that is, 20-fold greater than that among whites.⁴

The National Health and Nutrition Examination Surveys (1988 to 2002), or NHANES as it's called, another national population-based study, estimated that HIV rates among whites are low, 0.26% among 18 to 39 year olds, but much higher among blacks: 1% among young black women, 2.8% among older black women and even higher among black men, almost 2% among young black men and 4.5% among older black men.⁵

It's important to keep in mind that these figures estimate the U.S. civilian, non-institutionalized population and do not include either the homeless⁶ or the incarcerated,⁷ whose rates are substantially higher.

Male same-sex activity is the most frequent HIV transmission route noted by all men, including black men, but heterosexual transmission is more common among black men than men of other races and ethnicities.³ Among all women, including black women, sexual contact is the most common means of transmission.

HIV Susceptibility

Why are HIV rates so high among African Americans? One contributor is likely to be sexually transmitted infections [STIs] other than HIV. STIs facilitate HIV transmission⁸ and African Americans have high rates of several STIs.^9,10

For example, the black/white ratios in STI infection are 8 to 1 for chlamydia, 18 to 1 for gonorrhea,⁹ 6 to 1 for syphilis⁹ and about 3 to 1 for herpes simplex virus 2.¹⁰

In addition, bacterial vaginosis, which is not clearly an STI, is considerably more common among black women.¹¹ A growing body of evidence suggests that bacterial vaginosis increases the risk of acquiring HIV.^12,13 It's unclear how much other biological factors contribute to the racial disparity in HIV infection rates.

People who are homozygous for a 32-base pair deletion in the CCR5 gene are highly resistant to HIV infection.¹⁴ This mutation, actually quite uncommon among whites, at less than 1%, is even less common among African Americans.¹⁵ Heterozygosity of the CCR5 gene, a more frequent mutation than the homozygous state, is considerably more common among whites than blacks and may decrease susceptibility to HIV infection and slow the progression of the disease.

Another factor that may increase the risk of acquiring HIV is the prevalence of circumcision among African-American men, which, at 73%, is slightly lower than among white men, at 88%.¹⁶ We know that male circumcision decreases men's risk of acquiring HIV infection through vaginal intercourse.^17-19

Summary

To summarize some of the epidemiologic findings in the United States, blacks are disproportionately affected by AIDS and drivers of the epidemic among African Americans include:

• the high prevalence of other STIs that facilitate HIV transmission;
• the high background HIV prevalence that increases individuals' likelihood of acquiring HIV; and
• sexual network patterns, such as concurrent sexual partnerships and mixing among different risk-group subpopulations that promote population HIV spread.²⁰

It's important to remember that poverty, inequality and discrimination influence behavior, and also increase the risk of infection associated with behavior, as well as increase the infection risk independently of behavior.²¹ Finally, biological factors (such as distribution, CCR5 gene mutations and prevalence of circumcision) may play a role, although the extent of the influence these factors have is unclear.

Mortality and Morbidity

Let's talk briefly now about mortality and morbidity outcomes among African Americans with HIV infection. It's well known that HAART [highly active antiretroviral therapy] has markedly decreased mortality rates overall among patients with HIV.²² How has HAART impacted mortality and morbidity among African Americans? Robert S. Levine from Morehouse School of Medicine and Nathaniel C. Briggs from Meharry Medical College et al examined black/white differences in HIV disease mortality before and after the introduction of HAART.²³

For their data source they used the U.S. National Center for Health Statistics mortality file from 1990 through 2002 and examined HIV-related mortality among blacks and whites in 3,141 counties, parishes, independent cities and also in Washington, D.C.

The outcome of interest for this study was age and gender-specific black/white mortality rate ratios, as this measure reflects racial disparities and death rates. The investigators found that the black/white mortality rate ratio widened significantly after HAART was introduced. That is, racial disparities actually increased after HAART.

Racial disparities in mortality rates were particularly great among women and the elderly. Black women in all age groups had about a 13-fold greater risk of dying from HIV compared to white women of the same age range. Older black women were at especially high risk. Black women age 65 through 74 had a greater than 20-fold risk of death compared to white women.

Among men, racial disparities were also significant, but in only one age group, that of men between the ages of 75 and 84, with black men's relative risk greater than 13 times that of white men.

County-level socioeconomic indicators (for example, indices of inequality, such as the black/white poverty rate ratio, and demographic indicators, such as the proportion of black residents) were important predictors of post-HAART disparities among black men, and black mortality in general. In fact, pre-HAART era mortality rates predicted post-HAART era mortality among black men.

It's also noteworthy that the mortality rate ratio varied among communities. Communities had different vulnerabilities to disparity. It was concluded that unequal diffusion of HAART into U.S. communities occurred perhaps due to factors such as a lack of health insurance, inequalities in care and differential referral to clinical trials. This may have rendered some communities more vulnerable than others to racial disparities.

Early in the HAART era, some studies, such as results from the HIV Cost and Services Utilization Study, indicated that blacks were less likely to receive HAART.^24,25 Unfortunately, even though we're further along in the HAART era, more recent studies continue to support these findings.^26-28

Kelly A. Gebo from Johns Hopkins University School of Medicine and other investigators for a multi-state, multi-site patient cohort -- 10 U.S. HIV primary care sites in the HIV Research Network -- examined this issue.²⁸ The authors considered patients eligible for HAART if the patients had at least two CD4+ cell counts under 350 cells/mm³. They found that 91% of eligible patients received HAART. However, demographic disparities were noted. African Americans, injection drug users and patients who were uninsured or who had private insurance were less likely to receive HAART. Blacks were less likely to receive HAART, even after controlling for outpatient utilization and number of CD4+ cell tests.

At the Conference on Retroviruses and Opportunistic Infections [CROI] in Boston in 2008, Frank Palella and colleagues presented an interesting study on this topic.²⁷ They examined mortality risk among more than 2,000 patients enrolled in the HIV Outpatient Study [HOPS] in seven cities in the United States from 1999 through 2005. Patients were followed for a mean of 5.9 years.

People with public insurance were found to be more likely to die than those who had non-public insurance, and non-Hispanic blacks were more likely to die than either Hispanics or non-blacks.

Non-Hispanic black race or ethnicity, increased age and a lower CD4+ cell count at HAART initiation were independently associated with increased mortality risk in multi-variable analysis. CD4+ cell count at HAART initiation was lower for people who were publicly insured compared to those who were non-publicly insured and for non-Hispanic blacks compared to non-blacks.

Is differential access to care the problem? In another study also presented at CROI this year, Amy Weintrob from Walter Reed Army Medical Center et al examined mortality differentials in a setting with equal access to care.²⁹ In the longitudinal, U.S. military cohort with 1,031 participants who started HAART between 1996 and 2006, 73% of whites and 59% of blacks achieved suppression six months after starting drugs. A number of factors that one would expect to be associated with an increased likelihood of virologic suppression were, in fact, independently associated with that outcome in this study. They included having:

• a lower baseline viral load,
• a higher nadir CD4+ cell count,
• no prior AIDS event, and
• no prior antiretroviral use.

All those factors were more likely to result in virologic suppression.

More difficult to explain was race. Whites were more likely to achieve virologic suppression, with an odds ratio of about two. It's noteworthy that there were no racial/ethnic differences in:

1. initial regimens or regimens that were given six months after the initial regimen; or
2. the proportions of patients who changed or stopped their HAART regimens.

These differences with regards to virologic suppression persisted over time, as well. At 12 months, whites were still more likely to have achieved virologic suppression with an odds ratio of 1.7.

The authors concluded that, despite access to free health care and starting similar HAART regimens, African Americans had only half the odds of European Americans of achieving viral suppression six months after starting HAART. Again, this difference persisted to 12 months and was not explained by discontinuations or changes in initial therapy.

Findings by Diana Lemly et al echo the results of the previously mentioned studies.³⁰ This study was a retrospective examination of all patients who were receiving care at the Comprehensive Care Center in Nashville from January 1998 to December 2005.

Blacks experienced significantly greater mortality than non-blacks. After adjusting for baseline demographic and clinical characteristics, death was associated with being female, black or an injection drug user. Importantly, blacks and women were less likely to receive antiretroviral therapy, even when their baseline CD4+ cell counts were less than 200 cells/mm³.

Summary

In the post-HAART era, blacks continue to disproportionately experience increased mortality compared to non-blacks. The disparities are substantial for men and women, and are especially great for women and the elderly. These disparities appear to relate in some degree to inequalities that are measurable at the contextual level, that is, at the neighborhood or county level, as opposed to only at the individual level.

Blacks are less likely to receive HAART and are less likely to achieve virologic suppression when they do receive HAART, even after adjusting for relevant clinical and demographic factors.

What does this mean for our practices? I think it means we need to work to ensure that we offer HAART to all our patients who need it and focus on our black patients who are eligible for treatment and try to support them in accessing it (for example, through facilitating their consultation with effective social service agencies, social workers and case management agencies, as well as by providing effective patient education).

Late Presentation to Care

Even with all the advances in HIV medicine, an ongoing problem still is that patients, in general, have been presenting later for care.

In a recent study, Jeanne C. Keruly and Richard D. Moore used the Johns Hopkins HIV clinical cohort to assess immune status and time of HIV diagnosis in antiretroviral-naive patients who presented for care between 1990 and 2006.³¹

The median presenting CD4+ cell count fell from 371 cells/mm³ during 1994 to 276 cells/mm³ during 2003 to 2006, overall, and also decreased within individual demographic groups.

Blacks had consistently lower CD4+ cell counts than whites at presentation for care. Although the median time from HIV diagnosis to presentation for care also decreased among blacks during 2003 through 2006, the median time to presentation for care was still more than 2.5 times as long as it was for whites.

These data have some implications for primary care providers. For one thing, routinization of HIV testing, as recommended by the CDC, will likely be beneficial in diagnosing some patients earlier and facilitating their earlier entry to HIV care.

Adherence

Now let's take a look at the role adherence has in virologic outcome among black patients. According to a couple of studies, the most recent one was by David R. Bangsberg, adherence reliably predicts virologic response.^32,33 The factors most consistently associated with nonadherence are: symptoms and adverse drug effects, psychological distress, lack of social or family support, complexity of the HAART regimen, low patient self-efficacy and inconvenience of treatment.

Characteristics that don't consistently correlate with antiretroviral therapy adherence include: sociodemographic characteristics, substance abuse, depressive symptoms, quality of life, CD4+ cell count, knowledge and beliefs about treatment, patients' satisfaction with health care and patient-provider relationship.

Bruce R. Schackman and colleagues took a look at the relationship between race, virologic failure, adherence and quality of life in ACTG [AIDS Clinical Trials Group] A5095.³⁴ In this landmark study, HIV-infected, treatment-naive patients were randomized to receive zidovudine/lamivudine [AZT/3TC, Combivir] plus efavirenz [EFV, Sustiva, Stocrin] versus zidovudine/lamivudine/abacavir [AZT/3TC/ABC, Trizivir] plus efavirenz versus zidovudine/lamivudine/abacavir alone.

The investigators used several different measures of adherence that indicated whether or not the participant reported perfect adherence during different recall periods (for example, the past four days, past weekend, past month, etc.). They also measured quality of life. Virologic failure was defined as the first of two successive viral loads greater than or equal to 200 copies/mL, at or after week 16. Virologic failure was associated with week 12 nonadherence during the past four days for blacks, but not for whites. Race-adherence interactions were also noted in other models of adherence, including missing at least one medication dose ever in the past month or the past weekend.

It's also worth noting that a lower quality of life was also an independent predictor of virologic failure, but the effect of quality of life on virologic failure did not vary by race.

The major message is that, in the patients who received an efavirenz-containing regimen, the penalty for nonadherence, virologic failure, was substantially greater among blacks than whites. This is important given efavirenz's important standing in the armamentarium of first-line antiretrovirals.

Efavirenz Pharmacogenetics

Given Schackman's findings, have racial differences in the pharmacogenetics of efavirenz -- which is metabolized mainly by cytochrome P450, the CYP2B6 gene³⁵ -- been reported? In fact, some studies have documented racial differences.^36-38 Numerous polymorphisms of this gene occur and the distribution of these polymorphisms varies somewhat by race/ethnicity.³⁹

For example, in G516T, a CYP2B6 genetic variant, the TT substitution occurs in 3.4% of whites, 20% of blacks and 6.7% of Hispanics.³⁶ This polymorphism is associated with decreased efavirenz clearance, with resultant increased plasma efavirenz levels and increased CNS [central nervous system] side effects during the first week of treatment.

In David Haas' analysis of ACTG study A5097s examining the pharmacogenetics of response to efavirenz, tolerance to CNS effects developed, despite persistently increased levels of the drug, and the TT substitution was not associated with virologic failure.³⁶

As I mentioned a moment ago, some CYP2B6 polymorphisms are associated with decreased plasma efavirenz clearance. Heather Ribaudo and her colleagues examined the relationships between the 516TT polymorphism and plasma efavirenz concentration-time profiles after stopping therapy.⁴⁰ They found efavirenz half-life increased -- doubled in some cases -- with some polymorphisms. The longest half-lives occurred with the TT genotype, which is more common, as I mentioned, in African Americans.

This increased half-life may predict increased risk of developing drug resistance among patients with this polymorphism who discontinue treatment with efavirenz. This finding is relevant to patients who stop an efavirenz-containing antiretroviral regimen and don't immediately start another effective regimen, but it's not relevant to people who promptly switch to another effective antiretroviral regimen upon discontinuing efavirenz.

Efavirenz has a long half-life and a low-genetic barrier to resistance.⁴⁰ So it's important not to simultaneously stop all drugs in efavirenz-containing regimens, since it may result in functional efavirenz monotherapy that selects for drug-resistant virus.⁴⁰ When you stop efavirenz, it needs to be replaced with a protease inhibitor, or some other antiretroviral, for a duration sufficient to ensure efavirenz clearance in order to minimize the chances of developing resistance.

Summary

In summary, blacks have a somewhat higher frequency of CYP2B6 gene polymorphisms that are associated with decreased efavirenz clearance and increased CNS adverse effects during their first week on efavirenz. Tolerance to these high levels develops, however.

Patients with these polymorphisms probably have a higher risk of developing resistance if they stop an efavirenz-containing regimen without starting another one. In addition, patients who are non-adherent to an efavirenz-containing regimen are more likely to develop virologic failure, and one wonders whether these polymorphisms are the reason why. Nevertheless, efavirenz is an important drug in the HIV armamentarium for blacks and whites, and it should be noted that despite the data that I just mentioned, in clinical practice, most black patients tolerate efavirenz well.⁴⁰

Adverse Effects of HAART

Abacavir Hypersensitivity Reaction

Let's now consider the adverse effects of other antiretrovirals. A few antiretrovirals only have adverse effects that vary slightly by race. For example, HLA-B*5701-positivity is associated with abacavir [ABC, Ziagen] hypersensitivity reaction.^41,42 Whites have a higher risk than blacks do -- about 5% to 8% -- for abacavir hypersensitivity reaction, but hypersensitivity reaction does also occur in blacks.^43,44 About 2% to 3% of blacks who are given abacavir experience a hypersensitivity reaction.^45,46

HLA-B*5701 testing, which has been found to be 100% sensitive as a marker for the abacavir hypersensitivity reaction in both blacks and whites, should be performed before prescribing abacavir.⁴² In other words, it should never be assumed that blacks have no risk of abacavir hypersensitivity.

Hyperpigmentation and Zidovudine and Emtricitabine

Other unusual adverse effects can occur. For example, with zidovudine [AZT, Retrovir], black patients occasionally experience reversible hyperpigmentation of the nails or oral mucosa, which can be upsetting.⁴⁷ Similarly, on rare occasions, emtricitabine [FTC, Emtriva] causes hyperpigmentation of the palms or soles.⁴⁸ This occurs in fewer than 2%, but when it occurs it does so almost exclusively in black patients.

Prevalence of Chronic Diseases

Comorbidities are an important determinant of survival in HIV-infected patients, especially blacks. Among blacks in the United States, cardiovascular disease occurs in 44.6% of men and 49% of women over age 20. Almost half of black women, about 49.7%, and more than a quarter of black men are obese.⁴⁹

To find the age-adjusted prevalence of hypertension among African Americans, the CDC analyzed data from NHANES during 1999 to 2002.⁵⁰ They found it was 40.5 and only 29.8% of non-Hispanic black adults over age 18 with hypertension had adequate blood pressure control. In another CDC analysis of NHANES data, this time from 1999 to 2000, the age-adjusted prevalence of diabetes was 14.9%.⁵¹ From 1990 to 2001, the incidence of end-stage renal disease among blacks was four times greater than among whites.⁵²

In the Palella et al HIV Outpatient Study that I mentioned earlier, you will recall that black patients were found to have higher mortality rates.²⁷ The authors found that non-AIDS causes of death -- many of which are preventable, such as cardiac disease, renal disease, diabetes and cancer -- caused the majority of deaths among all HIV-infected patients. This finding led the study's authors to conclude that modifiable health risks may contribute to racial disparities in death rates among HIV-infected patients.

Chronic Kidney Disease

I'd like to talk for a few minutes about some of the more recent findings concerning chronic kidney disease among black patients with HIV. Chronic kidney disease is defined as a GFR [glomerular filtration rate] of less than 60 mL/min/1.73 m² or evidence of kidney damage for more than three months.⁵³

Risk factors for chronic kidney disease among HIV-infected patients include factors present in the general population. These include diabetes, hypertension, race (specifically, being black) and other genetic factors, family history, hepatitis C virus [HCV] infection, use of cocaine, smoking cigarettes and atherosclerotic disease.⁵⁴ But risk factors among HIV-infected patients also include some factors that are unique to HIV infection, such as a lower CD4+ cell count and a higher HIV viral load.⁵⁵

Kidney biopsies of patients with chronic kidney disease reveal a number of causes of chronic kidney disease among HIV-infected patients.⁵⁶ HIV-associated nephropathy is a major cause.⁵⁷ Coinfection with hepatitis B virus [HBV], HCV or syphilis⁵⁸ can cause membranous nephropathy. HCV and mixed cryoglobulinemia can cause membranoproliferative glomerulonephritis.⁵⁹ Biopsies also reveal diabetic⁶⁰ and hypertensive nephropathies.⁵⁶ And immune complex glomerulonephritis results from production of IgA antibodies directed against HIV antigens.⁶¹

HIV-Associated Nephropathy

I alluded to HIV-associated nephropathy a moment ago. HIV-associated nephropathy, or HIVAN, is a collapsing focal segmental glomerulosclerosis that typically results in nephrotic syndrome.⁶² Among HIV-infected patients with chronic kidney disease who have undergone a renal biopsy, it has accounted for more than 60% of chronic kidney disease diagnoses. It results from direct HIV infection and gene expression, especially nef and vpr in tubular and glomerular epithelial cells.⁶²

HIVAN occurs almost exclusively among blacks. Prevalence among blacks is 12-fold greater than among whites.⁶³ It has a stronger association with black race than any other cause of renal failure except sickle cell anemia.⁶⁴ It's not that rare either.

In one study by Tejinder S. Ahuja et al, the prevalence of HIVAN among HIV-infected black patients was 3.5%.⁶⁵ The disease has an aggressive course with rapid progression to end-stage renal disease.⁵⁷ Ultrasound usually reveals normal to large echogenic kidneys, but a specific diagnosis requires biopsy.⁶² Among patients with HIVAN, antiretroviral therapy is associated with preserved renal function and prolonged survival.^66,67 A very important clinical issue is that, according to the current HIV treatment guidelines, HIVAN is an indication for antiretroviral therapy, regardless of CD4+ cell count.⁶⁸

A recent study suggests that the pace of kidney disease may differ between black and white HIV-infected patients.⁶⁹ Gregory M. Lucas and colleagues did an interesting study in a Baltimore Johns Hopkins HIV clinical cohort of HIV-infected patients. They found that blacks were at increased risk for incident chronic kidney disease with a significant hazard ratio of 1.9. After adjustment for other factors, specifically sex, age, AIDS status, injection drug use and calendar time, the association between race and chronic kidney disease fell a little to 1.65.

Once chronic kidney disease developed, blacks developed end-stage renal disease much faster than whites. The hazard ratio for development of end-stage renal disease among blacks was 17.7 compared to whites, and the GFR fell six times faster among blacks than whites.

These data suggest that, although the risk of chronic kidney disease is slightly higher in HIV-infected blacks than in whites, much of the markedly increased risk of end-stage renal disease among blacks is due to faster progression of chronic kidney disease once it starts. Indeed, blacks with chronic kidney disease had more aggressive disease features. For one thing, they were more likely to have high-grade proteinuria and, as I mentioned earlier, a faster GFR decline.

Summary

The Lucas et al study has some implications for our clinical practice. First, as the IDSA [Infectious Diseases Society of America] recommends, we should incorporate renal screening into routine HIV care.⁵⁶ In addition, the cohort study implies that ACE [angiotensin-converting enzyme] inhibitors and ARB [angiotensin receptor blocker] drugs decrease the risk of progression to end-stage renal disease in HIV-infected patients with chronic kidney disease.⁶⁹ Early identification of chronic kidney disease may maximize benefits of therapy. In addition, the serum creatinine-based GFR is a relatively insensitive marker of early kidney disease. It's recommended that we actually do urinalysis annually or quantify the urine protein/creatinine ratio. And finally, it raises a question of whether or not we should perhaps consider starting HAART earlier during the course of HIV disease.

Screening Algorithm for HIV-Related Renal Diseases

A few years ago, the IDSA published practice guidelines for renal screening and evaluation of HIV-infected patients.⁵⁶ According to these guidelines all HIV-infected patients should be screened with urinalysis for detection of proteinuria and serum creatinine to estimate creatinine clearance or GFR.

All patients should also undergo a qualitative assessment for risk of kidney disease, with evaluation of factors such as race, family history, CD4+ cell count, HIV viral load and history of use of nephrotoxic medications, as well as comorbidities such as diabetes, hypertension and HCV infection.

Black patients and patients with risk factors are considered high risk. If, upon screening, there is no proteinuria, those people at high risk should be screened annually. People who have neither proteinuria nor risk factors should be followed clinically. If screening studies are abnormal, that is greater than or equal to 1-plus proteinuria or a GFR less than 60 mL/min/1.73 m², the patient should receive a spot urine protein/creatinine ratio, a renal ultrasound and consideration of referral to a nephrologist for further evaluation and possibly for renal biopsy.

Summary

In summary, HIV-infected, black patients are at increased risk for renal disease. Among HIV-infected patients, renal disease appears to progress more rapidly among blacks than whites. More than half of chronic kidney disease diagnoses are due to HIV-associated nephropathy on biopsy. HIV-associated nephropathy occurs almost exclusively among blacks and is due to direct HIV infection. It's diagnosed definitively only by renal biopsy and is an indication for HAART, regardless of CD4+ cell count, so it's important to diagnose this. IDSA guidelines recommend annual screening, and, if appropriate, further work up for all black patients and others with risk factors for renal disease.

HIV/Hepatitis B Coinfection

I'll mention HBV infection very briefly, as coinfection has implications for HIV management. The Adult/Adolescent Spectrum of HIV Disease Project looked at 16,248 HIV-infected patients who are receiving care in 11 geographic areas in the United States. They found that the incidence of acute HBV infection was higher among black patients, but that the prevalence of chronic HBV infection was actually pretty similar among whites and blacks.⁷⁰

Liver-related mortality was found to be higher among those with HIV/HBV coinfection than those with either HIV alone or chronic HBV infection alone.⁷¹ The DHHS [U.S. Department of Health and Human Services] guidelines recommend that all HIV-infected patients be screened for HBV infection.⁶⁸ HBV vaccine should be given to people who are not immune to HBV. If persistent HBV infection is present, this informs the selection of HIV antiretroviral therapy.

All coinfected patients should abstain from alcohol, and they should receive a hepatitis A virus [HAV] vaccine if they're not immune. If treatment for HIV or HBV is needed, it's recommended that an antiretroviral therapy be prescribed that suppresses both viruses (for example, tenofovir [TDF, Viread] plus either emtricitabine or lamivudine [3TC, Epivir]). Tenofovir, emtricitabine or lamivudine monotherapy for HBV in coinfected patients should be avoided because of the risk of HBV resistance.

HIV/Hepatitis C Coinfection

Now, concerning HCV, the prevalence of HCV antibodies in the U.S. general population has been found to be greater among blacks than whites at 3.5% versus 1.8%, respectively.⁷² About 20% of patients with HCV clear the virus spontaneously after acute infection.⁷³

Blacks, symptomatic patients⁷⁴ and HIV-infected patients⁷⁵ are the least likely to spontaneously clear. After acute HCV infection, 80% of patients develop chronic HCV infection.⁷³ Twenty percent to 50% of those with chronic infection develop cirrhosis.

It's important to note that HIV infection accelerates the development of cirrhosis. There is an approximately 0% to 3% per year risk of developing hepatocellular cancer once cirrhosis develops.^76,77 The risk of developing hepatocellular cancer is greater with infection due to HCV genotype 1b than 2a or 2c.⁷⁸

Concerning HIV/HCV coinfection, all HIV-infected patients should be screened for HCV infection, including those with normal LFTs [liver function tests].⁶⁸ Significant liver fibrosis has been reported in 25% to 40% of coinfected patients with a normal ALT [alanine transaminase] level,^79,80 a prevalence higher than the 10% to 30% of fibrosis reported in HCV-monoinfected individuals.^81,82 In two recent studies, 12% to 14% of coinfected patients with normal ALT had cirrhosis on liver biopsy.^82,83 All patients with HCV infection should abstain from alcohol, and receive HAV and HBV vaccines if they're not immune; they should also be evaluated for HCV therapy.

The indications for HCV therapy among people who are HIV-uninfected are: detectable plasma HCV RNA and bridging or portal fibrosis on liver biopsy.⁸⁴ Again, it's important to note that ALT levels don't accurately reflect the severity of HIV-associated liver disease. There are contraindications to pegylated interferon and ribavirin [Copegus, Rebetol]: for example, pregnancy, refusal to use contraception, decompensated liver disease, renal insufficiency, untreated major depression and advanced cardiopulmonary disease.

Pegylated interferon plus ribavirin results in the highest rates of HCV clearance in HIV-infected patients, and they typically have about a 27% to 40% sustained viral response.^85-87 Predictors of sustained viral response among coinfected patients are: having HCV genotype 2 or 3 and a low baseline HCV viral load.⁸⁸ Host factors are also predictors, and these include younger age, lower body mass index, lack of insulin resistance and non-black ethnicity. Black patients are less likely to have a sustained viral response. HCV status and treatment schedule (for example, getting optimal doses of pegylated interferon and/or ribavirin, having a long enough duration of therapy and good adherence) are also all predictors.

Summary

In summary, it's important to screen all patients for coinfection with HBV and HCV. Patients who are not immune to HAV and HBV should be vaccinated. Coinfected patients should be advised to abstain from alcohol. Knowledge of HBV coinfection informs selection of HIV treatment to decrease the possibility of selecting for HBV resistance. Patients with HCV infection should be evaluated for treatment of this virus.

Conclusion

The advent of HAART has decreased death rates from HIV, but, as you can see, substantial racial disparities in virologic outcomes and mortality still persist, even among patients who receive HAART.

The pharmacology of drugs is generally similar among blacks and whites, with a few exceptions: Blacks are more likely to have genetic polymorphisms that result in decreased efavirenz clearance and appear more likely to have virologic failure when they don't adhere to efavirenz than non-adherent whites.

Blacks with HIV are more likely than whites to have comorbid conditions, such as diabetes, obesity and chronic kidney disease, that complicate their HIV management. Among patients with chronic kidney disease, blacks are more likely than whites to progress to end-stage renal disease. Moreover, HIV-associated nephropathy, which can have a particularly aggressive course, occurs almost exclusively among blacks. HIV-associated nephropathy is an indicator for initiation of HAART, regardless of CD4+ cell count. Liver disease is an important cause of mortality among patients with HIV, and HCV infection, a major cause of HIV-related liver mortality, is more common among African Americans.

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