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Prevalence of drug resistance mutations and HIV type 1 subtypes in an HIV type 1-infected cohort in rural Tanzania.

ABSTRACT: The development of resistance mutations in drug-targeted HIV-1 genes compromises the success of antiretroviral therapy (ART) programs. Genotyping of these mutations enables adjusted therapeutic decisions both at the individual and population level. We investigated over time the prevalence of HIV-1 primary drug resistance mutations in treatment-naive patients and described the HIV-1 subtype distribution in a cohort in rural Tanzania at the beginning of the ART rollout in 2005-2007 and later in 2009. Viral RNA was analyzed in 387 baseline plasma samples from treatment-naive patients over a period of 5 years. The reverse transcriptase (RT) and protease genes were reversely transcribed, polymerase chain reaction (PCR) amplified, and directly sequenced to identify HIV-1 subtypes and single nucleotide polymorphisms associated with drug resistance (DR-SNPs). The prevalence of major DR-SNPs in 2005-2007 in the RT gene was determined: K103N (5.0%), Y181C (2.5%), M184V (2.5%), and G190A (1.7%), and M41L, K65KR, K70KR, and L74LV (0.8%). In samples from 2009 only K103N (3.3%), M184V, and T215FY (0.8%) were detected. Initial frequencies of subtypes C, A, D, and recombinants were 43%, 32%, 18%, and 7%, respectively. Later similar frequencies were found except for the recombinants, which were found twice as often (15%), highlighting the subtype diversity and a relatively stable subtype frequency in the area. DR-SNPs were found at initiation of the cohort despite very low previous ART use in the area. Statistically, frequencies of major mutations did not change significantly over the studied 5-year interval. These mutations could reflect primary resistances and may indicate a possible risk for treatment failure.

SUBMITTER: Masimba P

PROVIDER: S-EPMC3749719 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Prevalence of drug resistance mutations and HIV type 1 subtypes in an HIV type 1-infected cohort in rural Tanzania.

Masimba Pax P Kituma Elimsaada E Klimkait Thomas T Horvath Edit E Stoeckle Marcel M Hatz Christoph C Mossdorf Erick E Mwaigomole Emmanuel E Khamis Salim S Jullu Boniphace B Abdulla Salim S Tanner Marcel M Felger Ingrid I

AIDS research and human retroviruses 20130901 9

The development of resistance mutations in drug-targeted HIV-1 genes compromises the success of antiretroviral therapy (ART) programs. Genotyping of these mutations enables adjusted therapeutic decisions both at the individual and population level. We investigated over time the prevalence of HIV-1 primary drug resistance mutations in treatment-naive patients and described the HIV-1 subtype distribution in a cohort in rural Tanzania at the beginning of the ART rollout in 2005-2007 and later in 20 ...[more]

PMID: 23806135

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Project description:BackgroundIn sub-Saharan Africa, diagnosis and management of extrapulmonary tuberculosis (EPTB) in people living with HIV (PLHIV) remains a major challenge. This study aimed to characterize the epidemiology and risk factors for poor outcome of extrapulmonary tuberculosis in people living with HIV (PLHIV) in a rural setting in Tanzania.MethodsWe included PLHIV >18 years of age enrolled into the Kilombero and Ulanga antiretroviral cohort (KIULARCO) from 2013 to 2017. We assessed the diagnosis of tuberculosis by integrating prospectively collected clinical and microbiological data. We calculated prevalence- and incidence rates and used Cox regression analysis to evaluate the association of risk factors in extrapulmonary tuberculosis (EPTB) with a combined endpoint of lost to follow-up (LTFU) and death.ResultsWe included 3,129 subjects (64.5% female) with a median age of 38 years (interquartile range [IQR] 31-46) and a median CD4+ cell count of 229/μl (IQR 94-421) at baseline. During the median follow-up of 1.25 years (IQR 0.46-2.85), 574 (18.4%) subjects were diagnosed with tuberculosis, whereof 175 (30.5%) had an extrapulmonary manifestation. Microbiological evidence by Acid-Fast-Bacillus stain (AFB-stain) or Xpert® MTB/RIF was present in 178/483 (36.9%) patients with pulmonary and in 28/175 (16.0%) of patients with extrapulmonary manifestations, respectively. Incidence density rates for pulmonary Tuberculosis (PTB and EPTB were 17.9/1000person-years (py) (95% CI 14.2-22.6) and 5.8/1000 py (95% CI 4.0-8.5), respectively. The combined endpoint of death and LTFU was observed in 1058 (33.8%) patients, most frequently in the subgroup of EPTB (47.2%). Patients with EPTB had a higher rate of the composite outcome of death/LTFU after TB diagnosis than with PTB [HR 1.63, (1.14-2.31); p = 0.006]. The adjusted hazard ratios [HR (95% CI)] for death/LTFU in EPTB patients were significantly increased for patients aged >45 years [HR 1.95, (1.15-3.3); p = 0.013], whereas ART use was protective [HR 0.15, (0.08-0.27); p <0.001].ConclusionsExtrapulmonary tuberculosis was a frequent manifestation in this cohort of PLHIV. The diagnosis of EPTB in the absence of histopathology and mycobacterial culture remains challenging even with availability of Xpert® MTB/RIF. Patients with EPTB had increased rates of mortality and LTFU despite early recognition of the disease after enrollment.

Project description:BACKGROUND:Access to antiretroviral therapy (ART) has increased dramatically in Sub-Saharan Africa. In Kenya, 560,000 people had access to ART by the end of 2011. This scaling up of ART has raised challenges to the Kenyan health system due to emergence of drug resistant viruses among those on treatment and possible onward transmission. To counter this, and come up with an effective treatment strategy, it has become vital to determine baseline mutations associated with drug resistance among the circulating strains of HIV-1 in Kenya. METHODS:The prevalence of mutations associated with drug resistance in HIV-1 protease (PR) and reverse transcriptase (RT) regions from 188 HIV-1 infected treatment-naïve pregnant women was investigated in Kapsabet, Nandi Hills and Kitale district hospitals of Kenya. Blood samples were collected between April 2005 and June 2006. The HIV-1 pol gene was amplified using primers for HIV-1 PR and RT and sequenced using the BigDye chemistry. The mutations were analyzed based on the IAS algorithm as well as the Stanford University HIV Drug Resistance Database. RESULTS:Based on the PR and RT sequences, HIV-1 subtypes A1 (n=117, 62.2%), A2 (n=2, 1.1%), D (n=27, 14.4%), C (n=13, 6.9%), G (n=3, 1.6%), and possible recombinants (n=26, 13.8%) were detected. Mutations associated with nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside RTI (NNRTI)-resistance were detected in 1.6% (3 of 188) and 1.1% (2 of 188), respectively. Mutations associated with PI resistance were detected in 0.5% (1 of 188) of the study population. CONCLUSION:The prevalence of drug resistance among drug-naïve pregnant women in rural North Rift, Kenya in 2006 was 3.2%. Major drug resistance mutations associated with PIs, NRTIs and NNRTIs do exist among treatment-naïve pregnant women in North Rift, Kenya. There is a need for consistent follow-up of drug-naïve individuals in this region to determine the impact of mutations on treatment outcomes.

Project description:BACKGROUND: Access to antiretroviral drugs for HIV-1 infection has increased in sub-Saharan Africa (SSA) during the past few years. Mutations in the HIV-1 genome are often associated with treatment failure as indicated by viral replication and elevated levels of virus in the blood. Mutations conferring resistance to antiretroviral drugs are based on comparing gene sequences with corresponding consensus sequences of HIV-1 subtype B that represents only 10% of the AIDS pandemic. The HIV pandemic in SSA is characterized by high viral genetic diversity. Before antiretroviral drugs become more widely available, it is important to characterize baseline naturally occurring genetic mutations and polymorphisms associated with antiretroviral drug resistance among circulating HIV-1 subtypes. METHODS: The prevalence of mutations associated with antiretroviral drug resistance in protease (PR) and reverse transcriptase (RT) regions among antiretroviral treatment-naïve HIV-1 infected pregnant women was investigated in Bukoba (Kagera) and Moshi (Kilimanjaro) municipalities, Tanzania, between September and December 2005. The HIV-1 pol gene was amplified using primers recognizing conserved viral sequences and sequenced employing BigDye chemistry from 100 HIV-1 seropositive treatment-naïve pregnant women and 61 HIV-1 seropositive women who had received a single dose of Nevirapine (sdNVP). Positions 1-350 of the RT and 1-99 of the PR genes were analyzed for mutations based on the Stanford University HIV Drug Resistance Database. RESULTS: HIV-1 subtypes A, C, D, CRF10_CD and Unique Recombinant Forms (URF) were detected. Primary mutations associated with NRTI and NNRTI resistance were detected among 3% and 4% of treatment-naïve strains, respectively. Primary mutations associated with NRTI and NNRTI resistance were detected in 1.6% and 11.5% of women who had received sdNVP, respectively. None of the primary mutations associated with PI resistance was found. Polymorphisms detected in RT and PR sequences were mainly mutations that are found in the consensus sequences of non-B subtypes CONCLUSION: Based on the WHO HIV Drug Resistance Research Network Threshold of less than 5%, the baseline prevalence of primary mutations among treatment-naïve HIV-1 infected pregnant women in Kagera and Kilimanjaro regions was low. The significance of HIV-1 subtype B polymorphic positions with respect to antiretroviral resistance identified among the prevalent HIV-1 subtypes is unknown. More studies addressing the correlation between polymorphic mutations, antiretroviral resistance and clinical outcome are warranted in regions where non-B subtypes are prevalent.

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Prevalence of drug resistance mutations and HIV type 1 subtypes in an HIV type 1-infected cohort in rural Tanzania.

Publications

Prevalence of drug resistance mutations and HIV type 1 subtypes in an HIV type 1-infected cohort in rural Tanzania.

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