Jean Louis Sankalé

Immunologic Criteria Are Poor Predictors of Virologic Outcome: Implications for HIV Treatment Monitoring in Resource-Limited Settings

BACKGROUNDnViral load (VL) quantification is considered essential for determining antiretroviral treatment (ART) success in resource-rich countries. However, it is not widely available in resource-limited settings where the burden of human immunodeficiency virus infection is greatest. In the absence of VL monitoring, switches to second-line ART are based on World Health Organization (WHO) clinical or immunologic failure criteria.nnnMETHODSnWe assessed the performance of CD4 cell criteria to predict virologic outcomes in a large ART program in Nigeria. Laboratory monitoring consists of CD4 cell count and VL at baseline, then every 6 months. Failure was defined as 2 consecutive VLs >1000 copies/mL after at least 6 months of ART. Virologic outcomes were compared with the 3 WHO-defined immunologic failure criteria.nnnRESULTSnA total of 9690 patients were included in the analysis (median follow-up, 33.2 months). A total of 1225 patients experienced failure by both immunologic and virologic criteria, 872 by virologic criteria only, and 1897 by immunologic criteria only. The sensitivity of CD4 cell criteria to detect viral failure was 58%, specificity was 75%, and the positive-predictive value was 39%. For patients with both virologic and immunologic failure, VL criteria identified failure significantly earlier than CD4 cell criteria (median, 10.4 vs 15.6 months; P < .0001).nnnCONCLUSIONSnBecause of the low sensitivity of immunologic criteria, a substantial number of failures are missed, potentially resulting in accumulation of resistance mutations. In addition, specificity and predictive values are low, which may result in large numbers of unnecessary ART switches. Monitoring solely by immunologic criteria may result in increased costs because of excess switches to more expensive ART and development of drug-resistant virus.

Impact of Hepatitis B Virus Infection on Human Immunodeficiency Virus Response to Antiretroviral Therapy in Nigeria

BACKGROUNDnAs highly active antiretroviral therapy (ART) is introduced into areas of the world in which hepatitis B virus (HBV) infection is highly endemic, it is important to determine the influence of HBV on persons with human immunodeficiency virus (HIV) and HBV coinfection who are receiving ART.nnnMETHODSnWe studied 1564 HIV-infected patients in Jos, Nigeria, who initiated ART. Participants with HIV-HBV coinfection had hepatitis B e antigen (HBeAg) and HBV DNA status determined. CD4+ T cell count and HIV load at ART initiation were compared between individuals with HIV monoinfection and those with HIV-HBV coinfection with use of univariate methods. Regression analyses were used to determine if HBeAg status or HBV DNA at ART initiation were associated with baseline HIV parameters or ART response.nnnRESULTSnThe median CD4+ T cell count of the 262 participants with HIV-HBV coinfection (16.7%) was 107 cells/mL, compared with 130 cells/mL for participants with HIV monoinfection at ART initiation (P = .001). Participants with HIV-HBV coinfection also had higher HIV loads than did patients with HIV monoinfection (4.96 vs 4.75 log10 copies/mL; p = .02 ). Higher HBV DNA and detectable HBeAg levels were independently associated with lower CD4+ T cell counts at ART initiation but not with higher HIV loads. In a multivariable model, HBeAg-positive patients were less likely than HBeAg-negative patients to suppress HIV replication to <or= 400 copies/mL (odds ratio, 0.54; P = .03 ) at 24 weeks, but they had similar CD4+ T cell increases. At 48 weeks, there was no significant effect of HBeAg status on ART response.nnnCONCLUSIONSnAmong HIV-infected Nigerian individuals, HBV coinfection, especially among those with high levels of HBV replication, was associated with lower CD4+ T cell counts at ART initiation, independent of HIV RNA level. Patients with HBeAg-positive status had a slower virological response to ART, compared with HBeAg-negative patients. Further work is needed to understand the effects of HBV on CD4+ T cells.

Intrapatient Diversity and Its Correlation with Viral Setpoint in Human Immunodeficiency Virus Type 1 CRF02_A/G-IbNG Infection

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) viral setpoint during the disease-free interval has been strongly associated with future risk of disease progression. An awareness of the correlation between viral setpoint and HIV-1 genetic evolution over time is important in the understanding of viral dynamics and infection. We examined genetic diversity in HIV-1 CRF02_A/G-IbNG-infected seroincident women in Dakar, Senegal; determined whether a viral setpoint kinetic pattern existed for CRF02_A/G-IbNG during the disease-free interval; and correlated viral load level and diversity. Samples were drawn during the disease-free interval from consenting CRF02_A/G-IbNG-infected, antiretroviral therapy-naïve female commercial sex workers in Dakar, Senegal. Based on sequential plasma RNA values, low and high viral setpoint groups were established. Intrapatient diversity and divergence over time was determined from earlier and later time point DNA samples from each person. Most individuals followed the viral setpoint paradigm. For each 1|−|log10 copy/ml of plasma increase in viral load, intrapatient diversity increased by 1.4% (P = 0.028). A greater diversification rate was observed in the high viral setpoint group than in the low viral setpoint group (P = 0.01). Greater nucleotide (P = 0.015) and amino acid (P = 0.048) divergences and a greater nucleotide divergence rate (P = 0.03) were found in the high viral setpoint group. There was no difference between the groups in the ratio of the number of nonsynonymous substitutions per nonsynonymous site to the number of synonymous substitutions per synonymous site. The greater intrapatient diversity, divergence, and diversification rates observed in the high viral setpoint group supports the notion that diversity is driven by cycles of viral replication resulting in accumulated mutations. Recognizing diversity potential based on viral load levels in individuals may inform the design of vaccines and therapies.

HIV infection among pregnant women in Nigeria

Objectives: To determine risk factors for HIV among pregnant women (N = 2657) receiving antenatal services in Jos, Plateau state, Nigeria. Methods: Information about potential risk factors was obtained at interview. Biological samples were collected for detection of HIV and other sexually transmitted infections (STIs). Results: The prevalence of HIV was 8.2%. Women aged 20–29 years had more than 4‐fold increased risk of HIV. Women of Catholic (adjusted odds ratio (AOR) = 1.72, 95% CI = 1.01–2.95) and Pentecostal (AOR = 2.57, 95% CI = 1.46–4.52) denominations were more likely to be HIV‐infected when compared to Moslem women. The risk of HIV was also increased among women with multiple marriages and in women married to a banker/accountant. Other predictors of HIV were having a husband with other partners, perceived risk of HIV, STIs, candidiasis and bacterial vaginosis. Conclusions: Development of effective interventions, including behavioral change, expansion of perinatal HIV prevention services and STI control, should be given the highest priority.

Impact of HIV type 1 subtype on drug resistance mutations in Nigerian patients failing first-line therapy.

A diverse array of non-subtype B HIV-1 viruses circulates in Africa and dominates the global pandemic. It is important to understand how drug resistance mutations in non-B subtypes may develop differently from the patterns described in subtype B. HIV-1 reverse transcriptase and protease sequences from 338 patients with treatment failure to first-line ART regimens were evaluated. Multivariate logistic regression was used to examine the effect of subtype on each mutation controlling for regimen, time on therapy, and total mutations. The distribution of HIV-1 subtypes included CRF02_AG (45.0%), G (37.9%), CRF06_cpx (4.4%), A (3.6%), and other subtypes or recombinant sequences (9.2%). The most common NRTI mutations were M184V (89.1%) and thymidine analog mutations (TAMs). The most common NNRTI mutations were Y181C (49.7%), K103N (36.4%), G190A (26.3%), and A98G (19.5%). Multivariate analysis showed that CRF02_AG was less likely to have the M41L mutation compared to other subtypes [adjusted odds ratio (AOR)u2009=u20090.35; pu2009=u20090.022]. Subtype A patients showed a 42.5-fold increased risk (AORu2009=u200942.5, pu2009=u20090.001) for the L210W mutation. Among NNRTI mutations, subtype G patients had an increased risk for A98G (AORu2009=u20092.40, pu2009=u20090.036) and V106I (AORu2009=u20096.15, pu2009=u20090.010), whereas subtype CRF02_AG patients had an increased risk for V90I (AORu2009=u20093.16; pu2009=u20090.003) and a decreased risk for A98G (AORu2009=u20090.48, pu2009=u20090.019). Five RT mutations were found to vary significantly between different non-B West African subtypes. Further study to understand the clinical impact of subtype-specific diversity on drug resistance will be critically important to the continued success of ART scale-up in resource-limited settings.

Rapid HIV testing and counselling in labour in a northern Nigerian setting.

Between April and August 2004, all pregnant women in labour at JUTH, were offered rapid HIV testing and counselling with opportunity to decline testing. HIV positive women were offered the standard nevirapine mono-therapy prophylaxis regimen (HIVNET 012). Four hundred and thirty (99.8%) of the 431 pregnant women who were offered rapid HIV testing and counselling, agreed to test. A sero-conversion rate of 2.1% (5 of 235) was found among women who had previously tested negative for HIV during the index pregnancy. A seroprevalence rate of 9.6% (16 of 166) was found among women with unknown HIV status. One patient who had an indeterminate HIV status prior to labour tested positive in labour. Rapid HIV testing and counselling in labour is a useful practice in high prevalence settings since it detects a substantial number of HIV-infected women and HIV-exposed babies that would otherwise have missed interventions to prevent MTCT.

Impact of hepatitis C virus on HIV response to antiretroviral therapy in Nigeria.

Abstract:The effect of hepatitis C virus (HCV) on antiretroviral therapy (ART) response in patients in sub-Saharan Africa is unknown. We studied 1431 HIV-infected ART initiators in Jos, Nigeria, of whom 6% were HCV coinfected. A similar proportion of HIV/HCV-coinfected and HIV-monoinfected patients achieved HIV RNA <400 copies per milliliter after 24 and 48 weeks of ART (P > 0.05). Hepatotoxicity was uncommon (0.8% and 0.33% at 24 and 48 weeks, respectively) but was more common in the HIV/HCV-coinfected group at 24 (adjusted odds ratio = 19.3; 95% confidence interval: 4.41 to 84.4) and 48 weeks (adjusted odds ratio = 56.7; 95% confidence interval: 5.03 to 636.92). HCV did not significantly impact ART response in this Nigerian cohort.

Interplay of Reverse Transcriptase Inhibitor Therapy and Gag p6 Diversity in HIV Type 1 Subtype G and CRF02_AG

Abstract The gag p6 region of HIV-1 has various nonsubstitutionary mutations, including insertions, duplications, deletions, and premature stop codons. Studies have linked gag p6 mutations to reduced susceptibility to antiretroviral therapy in HIV-1 subtype B. This study examined the relationship between antiretroviral therapy and gag p6 diversity in HIV-1 CRF02_AG and subtype G. p6 data were generated for secondary analyses following Viroseq genotyping of pol gene sequences in plasma samples from HIV-1-infected Nigerians on reverse transcriptase inhibitor therapy, with virologic failure (repeat VL > 2000 copies/ml). p6 sequence chromatograms were available for 40 CRF02_AG and 43 subtype G-infected individuals. Subjects who had not received their supply of antiretroviral drugs for at least 2 months prior to the plasma sampling were classified as nonadherent. p6 sequences from therapy-adherent individuals had more nonsubstitutionary mutations than sequences from drug-naive individuals (p = 0.0005). The P5L/T mutation was inversely correlated with the presence of K27Q/N in p6, with each mutation being more prominent in subtype G and CRF02_AG, respectively. The data also suggested that P5L/T may be a compensatory mutation for the loss of an essential phosphorylation site in p6. In addition, there was an inverse association between P5L/T mutations in p6 and thymidine analog mutations in reverse transcriptase (p = 0.0001), and drug nonadherence was associated with an 8-fold lower risk of having a nonsubstitutionary mutation in p6 (95% CI = 1.27-52.57). Our data suggest that antiretroviral therapy influences gag p6 diversity, but further studies are needed to clarify these observations.