Treatment Recommendations for HIV-Infected Patients With Co-infections

Infection with human immunodeficiency virus (HIV) can result in immunosuppression, allowing opportunistic pathogens to cause disease. Certain opportunistic infections (OIs) are associated with increases in viral load, which may accelerate HIV progression or increase transmission of HIV.[1, 2, 3] These opportunistic infections were a major source of morbidity and mortality in patients with HIV infection before the development of effective antiretroviral therapy (ART) and still occur today, mostly in infected individuals who are not receiving ART. Opportunistic infections are a major cause of morbidity and mortality in HIV-infected patients; however, with the availability of ART, there is a decline in the incidence of opportunistic infections in both low- and high-income countries.[4, 5]

Please see HIV Infection and AIDS.

Patients with HIV infection are at a greater risk for hepatitis B virus (HBV) infection, due to the common route of transmission.

Patients with HIV infection are at a higher risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma than patients diagnosed with only chronic HBV infection.[6, 7]

Treatment of HIV infection may improve the virologic, histologic, and clinical evolution of chronic HBV infection.[8]

Several antiretroviral agents, such as emtricitabine (FTC), lamivudine (3TC), and tenofovir, have activity against HIV and HBV, whereasile others, such as entecavir, have limited activity against HIV but lead to the development of HIV-resistant strains if used alone.[9]

Prior to the initiation of ART, all patients who test positive for hepatitis B surface antigen (HBsAg) should be tested for hepatitis B virus (HBV) deoxyribonucleic acid (DNA) using a quantitative assay to determine the level of HBV replication.[6]

Chronic HBV is defined as testing positive for HBsAg on 2 occasions for more than 6 months[10] ; patients with chronic HBV infection already receiving ART active against HBV should undergo quantitative HBV DNA testing every 6-12 months.[6]

Routine screening and immunization are recommended for all patients infected with HIV to prevent primary HBV infection; however, the immune response to HBV vaccine is lower in patients with HIV infection than in uninfected patients, and postvaccination HBsAg must be tested to document immunity.[11, 12, 13, 14]

All patients with HBV/HIV coinfection must be assessed for hepatitis A virus (HAV) immunity and vaccinated if negative.[14]

Recommendations for patients requiring hepatitis B virus and HIV treatment

In patients with HIV and HBV coinfection, HBV infection should be treated only in conjunction with HIV infection. Treatment of HBV infection alone without addressing the HIV infection will lead to emergence of HIV strains that are resistant to nucleoside reverse-transcriptase inhibitors (NRTI).[15]

Only tenofovir is fully active for treatment in patients with known or suspected lamivudine-resistant HBV infection.[16] Tenofovir is considered a first-line agent in patients with chronic HBV infection because the virologic efficacy is high and the risk for HBV resistance is low. Tenofovir is available in 2 preparations, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). TDF can lead to renal impairment and bone loss. The TAF formulation is associated with less renal toxicity and less effect on bone density.[17]

In treatment-naive patients with HIV/HBV coinfection, a regimen containing TDF plus FTC or TDF plus 3TC should be used as the backbone of HIV therapy.

If TDF cannot be used, entecavir may be used to treat HBV infection; however, owing to its weak activity against HIV,[6] this is not considered an active component of the antiretroviral regimen. Lamivudine-resistant strains of HBV may rapidly develop resistance; therefore, a higher dose (1 g/day) is recommended with more frequent HBV viral load monitoring.

Emtricitabine and lamivudine show efficacy against HBV infection in both hepatitis B e antigen (HBeAg)–positive and HBeAg-negative patients, but these medications are associated with greater development of resistance. Adefovir has weaker antiviral activity than tenofovir in both HBeAg-positive and HBeAg-negative patients with chronic HBV infection. It has been found to be safe in HIV and associated with lower rates of resistance mutations compared with lamivudine.[18]

If the HIV therapy requires modification (eg, due to HIV virologic failure), the HBV-active antiretroviral must be continued and new antiretrovirals added to achieve HIV viral suppression.

Please see Hepatitis B.

Increased rates of cirrhosis in patients with hepatitis C virus (HCV) are attributable to various factors, including older age, alcoholism, male sex, and HIV infection; higher rates of progression to cirrhosis are seen in patients with HCV/HIV.[6]

HCV infection in patients with HIV infection can have significant consequences, including liver disease progression, liver fibrosis,  cirrhosis, increased rates of end-stage liver disease, and shortened lifespan after hepatic decompensation.[6, 19]

Genotype 1 accounts for approximately 75% of hepatitis C infections in the United States.[20]

Initial evaluation and treatment recommendations for patients with hepatitis C virus/HIV coinfections

Prior to initiating ART, screen patients with HIV infection for HCV using sensitive immunoassays licensed for the detection of antibody to HCV in blood; to confirm the presence of chronic infection, persons who are HCV seropositive should be tested for HCV ribonucleic acid (RNA) using a qualitative or quantitative assay.[21]

Advise patients with HCV/HIV to avoid alcohol and receive HAV and HBV vaccines, if screened negative via serology.[6]

Drug-induced liver injury (DILI) following ART is more common in HIV/HCV coinfection; eradication of HCV infection may decrease the likelihood of antiretrovirus-associated DILI.[6]

It is important to monitor alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at 1 month and then every 3 months after the initiation of ART.

ART should be started in persons co-infected with HCV and HIV in accordance with the recommendations for initiating ART in treatment-naive patients.[22, 23, 24] ART should be started at least 4-6 weeks before hepatitis C treatment is initiated.

The objective of HCV antiviral treatment is to cure the HCV infection, reflected by a sustained virologic response. Patients with HIV and HCV coinfection traditionally had lower response rates to HCV treatment with older regimen of ribavirin and peginterferon compared with individuals without HIV infection; however, patients with coinfection appear to have comparable sustained virologic response rates with all oral, direct-acting antiviral (DAA) combination therapy.

Special considerations for antiretroviral therapy in patients with hepatitis C virus/HIV coinfection

Special considerations for ART in patients coinfected with hepatitis C virus and HIV include the following:

Patients receiving or considering therapy with ribavirin should avoid didanosine, stavudine, and zidovudine.daclatasvir

Use caution with antiretroviral agents with the greatest risk of DILI (eg, nevirapine).

Assess patients with cirrhosis for signs of liver decompensation according to the Child-Turcotte-Pugh classification system; hepatically metabolized antiretroviral drugs may require dose modification or avoidance in patients with Child-Pugh class B and C disease.[6]

Treatment of both HCV and HIV can be complicated by drug interactions, drug toxicities, and pill burden. Many of the newer directly acting anti-HCV drugs have significant interactions with antiretroviral agents; however, ledipasvir with sofosbuvir and daclatasvir plus sofosbuvir have been demonstrated as efficacious.[25, 26]

Regimen selection for HCV infection can vary based on genotype, history of prior HCV treatment, stage of underlying liver fibrosis, and, in rare cases, the presence of baseline NS5A inhibitor resistance–associated substitutions.

Please see Hepatitis C. 

Tuberculosis (TB) is caused by Mycobacterium tuberculosis, which commonly affects the lungs, although it can also affect other parts of the body.

Patients with HIV infection are more likely to be affected by TB; HIV infection may increase the risk for progression from latent to active TB. The risk for TB begins in the first year following HIV infection. TB infection can occur at any CD4 cell count, though the risk increases with progressive immunodeficiency.[27]

All patients should be tested for latent TB infection (LTBI) at the time of HIV diagnosis and annually using skin testing or interferon-gamma release assay (IGRA).

Patients diagnosed with active TB should be started on TB treatment as soon as possible; recommendations for anti-TB treatment regimens in adults infected with HIV follow the same principles as recommendations for adults without HIV infection. Standard anti-TB regimens include isoniazid plus a rifamycin (rifampin or rifabutin) plus pyrazinamide plus ethambutol for 2 months, followed by isoniazid plus a rifamycin for 4-7 months.[4, 6, 28]

Weekly isoniazid plus rifapentine for 3 months (3HP) is now recommended as an alternative regimen for LTBI when provided as directly observed or self-administered therapy. Patients with LTBI who cannot receive isoniazid should receive daily rifampin monotherapy for 4 months.[27]

Symptoms may worsen among patients with active TB upon initiation of ART owing to immune reconstitution inflammatory syndrome (IRIS). Patients at high risk for IRIS should receive pre-emptive adjunctive prednisone with the initiation of ART.[27] In patients with baseline CD4 cell counts less than 100 cells/µL who are starting ART within 30 days of starting anti-TB therapy, prophylactic administration of prednisone during the first 4 weeks of ART initiation should be considered. This intervention may reduce the likelihood of IRIS.[29]

The timing of ART and anti-TB therapy must therefore be taken into consideration, as follows[30] :

• In patients with pulmonary TB and a CD4 cell count of less than 50 cells/µL, ART should be initiated as soon as possible and within 2 weeks of TB treatment initiation. This approach reduces the combined risk for an AIDS-defining illness and death, despite an increased risk for TB immune reconstitution inflammatory syndrome (IRIS).
• In patients with pulmonary TB and a CD4 count of 50 cells/µL or more, ART should be initiated within 8 weeks of TB treatment initiation. In the absence of severe disease, early ART is not associated with a decreased risk for AIDS or death, and later initiation of ART (eg, 8 weeks) is associated with a lower risk for IRIS regardless of baseline CD4 cell count.
• In patients with TB involving the CNS, ART should be delayed for the first 8 weeks of anti-TB therapy, regardless of CD4 count.

Decisions to use a regimen containing either rifampin or rifabutin should be made after considering potential drug interactions. Rifamycins, such as rifampin and rifabutin, are a major part of anti-TB regimens; rifampin is a strong inducer of CYP3A enzymes and is associated with drug interactions with antiretroviral agents, such as protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs); rifabutin is a weak inducer and can be used as an alternative to rifampin.[4, 6]  However, dose adjustments must always be considered. For patients undergoing treatment for active TB, starting ART with efavirenz or an integrase strand transfer inhibitor (INSTI) is preferred, owing to fewer interactions with rifampin.[6, 4] Nevirapine-based regimens should be avoided owing to a higher rate for treatment failure.

There is a potential for drug-induced hepatitis with antiretroviral and anti-TB drugs, so frequent monitoring is required for signs and symptoms of hepatitis; monitoring of liver enzymes is also necessary.

Please see Tuberculosis.