Christopher J. Hoffmann

Clinical implications of HIV and hepatitis B co-infection in Asia and Africa.

Hepatitis B virus (HBV) is the leading cause of chronic liver disease and liver-related death worldwide, with the majority of these cases occurring in areas of Africa and Asia where HBV prevalence is high. Many of the countries that are affected by hepatitis B are also affected by a high HIV burden, leading to frequent HIV/HBV co-infection. The consequences of co-infection, including increased liver-related morbidity and mortality, increased hepatitis B viral replication, immune reconstitution to HBV in the setting of antiretroviral therapy, and hepatotoxicity from antiretroviral drugs, are especially important in regions with expanding antiretroviral programmes. Little data, however, are available on HIV/HBV co-infection from regions with high chronic hepatitis B prevalence. This Review discusses the epidemiology, natural history, pathogenesis, and management of HIV/HBV co-infection from these areas. Topics for future research relevant to HIV/HBV co-infection in Africa and Asia are also highlighted.

Life Expectancies of South African Adults Starting Antiretroviral Treatment: Collaborative Analysis of Cohort Studies

Leigh Johnson and colleagues estimate the life expectancies of HIV positive South African adults who are taking antiretroviral therapy by using information from 6 programmes between 2001 and 2010.

Gender differences in survival among adult patients starting antiretroviral therapy in South Africa: a multicentre cohort study.

Morna Cornell and colleagues investigate differences in mortality for HIV-positive men and women on antiretroviral therapy in South Africa.

Hepatotoxicity in an African antiretroviral therapy cohort: The effect of tuberculosis and hepatitis B

Objective:Hepatotoxicity is a significant complication of antiretroviral therapy (ART). We assessed the incidence of and risk factors for hepatotoxicity among HIV-infected individuals on ART in South Africa. Design:We conducted a retrospective cohort study in a workplace HIV care program in South Africa which uses a first-line regimen of efavirenz, zidovudine, and lamivudine and provides routine clinical and laboratory monitoring. Methods:We included subjects with baseline and follow-up alanine transaminase and aspartate aminotransferase tests. Severe hepatotoxicity cases were identified during the first 12 months of ART. Potential risk factors, including concomitant medication use, tuberculosis, and hepatitis B and C, were determined from clinical records, database queries, and serological testing. Associations with hepatotoxicity were investigated using Cox proportional hazards modeling. Results:Of the 868 subjects (94% male, median age 41 years), the median nadir CD4 cell count was 136/μl, 25% received concomitant tuberculosis treatment during ART, and 17% of a randomly selected subset were positive for hepatitis B surface antigen (HBsAg). We identified 7.7 episodes of severe hepatotoxicity per 100 person-years. Tuberculosis treatment increased risk 8.5 fold, positive HBsAg 3.0 fold, and nadir CD4 cells count < 100/μl 1.9 fold. Importantly, the fraction of patients with severe hepatotoxicity on ART (4.6%) was similar to the fraction with liver enzyme elevations > 5 times the upper limit of normal before starting ART (4%). Conclusions:In this African ART cohort, we found a low incidence of and minimal morbidity due to hepatotoxicity. HBsAg and concomitant tuberculosis therapy significantly increased the risk of hepatotoxicity.

Hepatitis B Virus Infection and Response to Antiretroviral Therapy (ART) in a South African ART Program

BACKGROUND Coinfection with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) is common in Africa; however, the impact of HBV infection on the outcomes of antiretroviral therapy programs is unclear. We evaluated the impact of chronic hepatitis B on HIV virologic response, changes in CD4 cell count, hepatotoxicity, and mortality among Africans receiving highly active antiretroviral therapy (HAART). METHODS We conducted a retrospective cohort study involving a workplace HAART program in South Africa. Participants received HAART according to a protocol and were followed up for up to 72 weeks. On the basis of pre-HAART serum assays, patients were classified as being hepatitis B surface antigen (HBsAg) negative, HBsAg positive with a low HBV DNA level (</= 1 x 10(4) copies/mL), and HBsAg positive with a high HBV DNA level (> 1 x 10(4) copies/mL). The relationships between HBV status and HIV RNA suppression, change in CD4 cell count, mortality, and hepatotoxicity were assessed with use of regression techniques. RESULTS Five hundred thirty-seven individuals fulfilled the inclusion criteria; 431 (80.3%) of these patients were HBsAg negative, 60 (11.2%) were HBsAg positive with a low HBV DNA level, and 46 (8.6%) were HBsAg positive with a high HBV DNA level. All groups had similar rates of HIV RNA suppression (P = .61), CD4 cell count increases (P =.75), and mortality (17 total deaths; P=.11) for up to 72 weeks after the initiation of HAART. Baseline transaminase levels were highest in the group with high HBV DNA levels (P=.004). Hepatotoxicity was similar between the HBsAg-negative group and the group with low HBV DNA levels but was higher in the group with high HBV DNA levels (incidence rate ratio, 4.4). CONCLUSIONS We revealed that HBV status does not affect HIV RNA suppression, CD4 cell count response, or mortality during the first 72 weeks of HAART in an African setting. The risk of HBV-associated hepatotoxicity, however, is associated with the baseline HBV DNA level.

Hepatitis B and long-term HIV outcomes in coinfected HAART recipients.

Background:Chronic hepatitis B (CH-B) is common among HIV-infected individuals and increases liver-related mortality in the absence of HAART. The impact of CH-B on long-term HAART outcomes has not been fully characterized. Methods:To address this question, HAART initiators enrolled in the Multicenter AIDS Cohort Study were retrospectively analyzed. Patients were classified by hepatitis B category based on serology at the time of HAART initiation. The association of CH-B with mortality, AIDS-defining illnesses, CD4 cell rise, and HIV suppression was assessed using regression analysis. Results:Of 816 men followed for a median of 7 years on HAART, 350 were never hepatitis B virus (HBV) infected, 357 had past infection, 45 had CH-B, and 64 were only core-antibody positive. Despite HAART, AIDS-related mortality was the most common cause of death [8.3/1000 person-years (PYs)]. It was highest in those with CH-B (17/1000 PYs, 95% confidence interval 7.3, 42) and lowest among never HBV infected (2.9/1000 PYs, 95% confidence interval 1.4, 6.4). In a multivariable model, patients with CH-B had a 2.7-fold higher incidence of AIDS-related mortality compared with those never infected (P = 0.08). Non-AIDS-related mortality was also highest among those with CH-B (22/1000 PYs), primarily due to liver disease (compared to never infected, adjusted hazard ratio 4.1, P = 0.04). There was no significant difference in AIDS-defining events, HIV RNA suppression, and CD4 cell increase. Conclusion:In HIV-infected patients receiving long-term HAART, HBV status did not influence HIV suppression or CD4 cell increase. However, mortality was highest among those with CH-B and was mostly due to liver disease despite HBV-active HAART.

Viremia, resuppression, and time to resistance in human immunodeficiency virus (HIV) subtype C during first-line antiretroviral therapy in South Africa.

BACKGROUND Episodes of viremia are common in African antiretroviral therapy (ART) programs. We sought to describe viremia, resuppression, and accumulation of resistance during first-line combination ART (cART) in South Africa. METHODS Retrospective analysis of a cohort receiving zidovudine, lamivudine, and either efavirenz or nevirapine with human immunodeficiency virus (HIV) RNA monitoring every 6 months. We assessed viremia (HIV RNA >1000 copies/mL after initial HIV RNA response) and resuppression (HIV RNA <400 copies/mL after viremia). Genotypic resistance testing was performed using stored plasma on a subset of patients at first detection of viremia and subsequently among patients with persistent viremia. RESULTS Between 2002 and 2006, 3727 patients initiated cART (median CD4, 147 cells/mm(3)). Of 1007 patients who developed viremia, 815 had subsequent HIV RNA assays, and 331 (41%) of these resuppressed without regimen switch. At identification of viremia, 45 (66%) of 68 patients had HIV-1 drug resistance, 42 (62%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistance, 25 (37%) had M184V/I, and 4 (6%) had multi-nucleoside analogue drug mutations. By 12 months of persistent viremia among a subset of 14 patients with resistance testing to 12 months, 11 (78%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistance, 8 (57%) had M184V/I, and 2 (14%) had multi-nucleoside analogue drug mutations. Resistance was associated with a reduced probability of resuppression; however, 50% of patients with NNRTI resistance resuppressed while receiving an NNRTI. CONCLUSIONS The majority of patients had NNRTI resistance mutations at detection of viremia. However, 41% resuppressed without regimen switch. Our findings support maximizing first-line use while minimizing risk of significant cross-resistance by implementing intensive adherence support and repeat HIV RNA testing 3-6 months after detecting viremia, with regimen switch only if viremia persists.

Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: A multicentre retrospective cohort study

Summary Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene. Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27–1·77 for CD4 cell count <100 cells per μL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1·48, 95% CI 1·20–1·82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0·626]). Interpretation We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. Funding The Wellcome Trust.Summary Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase ( RT ) gene. Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27–1·77 for CD4 cell count Interpretation We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. Funding The Wellcome Trust.

Immunodeficiency at the start of combination antiretroviral therapy in low-, middle- and high-income countries

Objective:To describe the CD4 cell count at the start of combination antiretroviral therapy (cART) in low-income (LIC), lower middle-income (LMIC), upper middle-income (UMIC), and high-income (HIC) countries. Methods:Patients aged 16 years or older starting cART in a clinic participating in a multicohort collaboration spanning 6 continents (International epidemiological Databases to Evaluate AIDS and ART Cohort Collaboration) were eligible. Multilevel linear regression models were adjusted for age, gender, and calendar year; missing CD4 counts were imputed. Results:In total, 379,865 patients from 9 LIC, 4 LMIC, 4 UMIC, and 6 HIC were included. In LIC, the median CD4 cell count at cART initiation increased by 83% from 80 to 145 cells/&mgr;L between 2002 and 2009. Corresponding increases in LMIC, UMIC, and HIC were from 87 to 155 cells/&mgr;L (76% increase), 88 to 135 cells/&mgr;L (53%), and 209 to 274 cells/&mgr;L (31%). In 2009, compared with LIC, median counts were 13 cells/&mgr;L [95% confidence interval (CI): −56 to +30] lower in LMIC, 22 cells/&mgr;L (−62 to +18) lower in UMIC, and 112 cells/&mgr;L (+75 to +149) higher in HIC. They were 23 cells/&mgr;L (95% CI: +18 to +28 cells/&mgr;L) higher in women than men. Median counts were 88 cells/&mgr;L (95% CI: +35 to +141 cells/&mgr;L) higher in countries with an estimated national cART coverage >80%, compared with countries with <40% coverage. Conclusions:Median CD4 cell counts at the start of cART increased 2000–2009 but remained below 200 cells/&mgr;L in LIC and MIC and below 300 cells/&mgr;L in HIC. Earlier start of cART will require substantial efforts and resources globally.

Thyroid Function Abnormalities in HIV-Infected Patients

Abnormal thyroid function test results are common among human immunodeficiency virus (HIV)-infected patients. Although the prevalence of overt thyroid disease does not appear to be significantly increased in HIV-infected patients, compared with the general population, specific patterns of abnormal thyroid function test findings are more frequently identified among HIV-infected patients. Among patients with advanced acquired immunodeficiency syndrome, nonthyroidal illness (i.e., euthyroid sick syndrome) is common. During antiretroviral therapy, the prevalence of 2 generally asymptomatic conditions (subclinical hypothyroidism, which is characterized by isolated elevated thyroid-stimulating hormone levels, and isolated low free thyroxine levels) is increased. In addition, Graves disease, which is marked by low thyroid-stimulating hormone and elevated thyroxine levels, may occur during immune reconstitution. Testing for thyroid disease among symptomatic patients should begin with measurement of the thyroid-stimulating hormone level. However, there is insufficient evidence to recommend routine thyroid screening of asymptomatic HIV-infected individuals. This review summarizes the current evidence regarding the optimal laboratory evaluation of thyroid function; highlights the causes, presentation, and treatment of thyroid dysfunction in HIV-infected patients; and discusses the controversies regarding screening.